Purinyl-N-hydroxyl pyrimidine formamide derivative, preparation methods and uses thereof

ABSTRACT

The present invention relates to the field of the chemical medicines, and in particular, to purinyl-N-hydroxyl pyrimidine formamide derivatives, a preparation method therefor and a use thereof. The present invention provides a purinyl-N-hydroxyl pyrimidine formamide derivative having a structure represented by formula (I). The invention also provides a method for preparing said purinyl-N-hydroxyl pyrimidine formamide derivative and a use thereof. Purinyl-N-hydroxyl pyrimidine formamide derivative provided in the invention can be not only a PI3K and HDAC double-functional target kinase inhibitor, but also a PI3K or HDAC single target kinase inhibitor, thus providing new choice for preparing multi-target inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase Application ofPCT/CN2016/079022, filed Apr. 12, 2016, which claims priority from CN201510189476.9, filed Apr. 21, 2015, the contents of which applicationsare incorporated herein by reference in their entireties for allpurposes.

TECHNICAL FIELD

The Invention relates to the field of chemical medicines, andparticularly to a purinyl-N-hydroxyl pyrimidine formamide derivative,preparation methods and uses thereof.

BACKGROUND ART

Tumor is a kind of disease marked by cell malignant proliferation,having a complicated pathogenesis which often involves in heredity orepigenetic changes. The occurrence and development of tumor depend on avariety of receptors or signal transduction pathways, making theantineoplastic drugs which act on certain target point have to facefollowing problems as: 1) The tumor cells cannot be fully killed; 2) itis easy to have drug resistance. Currently, although multi-drugcombination has solved the above problems, it is likely to causeinteractions between drugs, generating unpredictable adverse reactions;moreover, the usage of each drug in the combination is different fromthat for separate use. Compared with the drug combination, themulti-target drug can avoid interactions between drugs and haveobviously better treatment effect than that of single-target drug.

In recent years, as the studies on malignant tumor are deepenedconstantly, more and more tumor signal pathways are found. Among which,the antineoplastic protocols with the signal transduction pathwaymediated by PI3K as the target point gradually become a study hotspot.The important role of PI3K/Akt/mTOR signal pathway played in theoccurrence and development of tumors has been proven in many studies andits function in lung cancer and liver cancer also has been reported.

Histone deacetylases (HDACs) are closely related to tumor; throughdeacetylation of histone N-lysine residues, gene transcriptionregulating and chromatin remodeling can be realized. In addition, HDACscan also catalyze non-histone deacetylation, such as p21, microtubulin,HSP90 (heat shock protein 90), etc. Inhibiting HDACs may induce cyclearrest, differentiation and apoptosis of tumor cells.

PI3K protein kinase and HDAC are the most important target points fortumor cell survival; HDAC inhibitor may have inhibition effect on tumorcell messenger multiple target points through epigenetic regulatorymechanism. The significant anti-cancer effect of PI3K inhibitor and HDACinhibitor has been verified clinically. Multiple HDAC inhibitors asvorinostat (SAHA), panobinostat (LBH589) and chidamide have come intothe market upon approval.

Based on the structure characteristics of PI3K kinase inhibitorGDC-0941, Qian C G et al. used the method of pharmacophore splicing,i.e., splicing the pharmacophores of PI3K kinase inhibitor and HDACIsinhibitor into a molecule. Through a great deal of in vivo/in vitroscreening, the most preferred compound CUDC-907 is found. It canpotently inhibit PI3Ks enzyme of Type I and HDAC enzyme of Type I & II,and its inhibition values to activities of HDAC1, HDAC2, HDAC3, HDAC8,HDAC6, HDAC10, HDAC11, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ are respectively1.7, 5.0, 1.8, 191, 27, 2.8, 5.4, 19, 54, 39 and 311 nM^([1]). Thesubsequent pharmacology experiment shows that, multiple signal pathwaysare decreased by inhibiting HDAC through CUDC-907 and the tumor cellgrowth is thus inhibited. For its favorable subsequent performance,Curis declared on Apr. 6, 2015 that FDA has granted CUDC-907 thequalification of orphan drug for treating diffuse large b-cell lymphoma.Such progress also promotes and encourages the research and developmentof DAC-kinase multi-target inhibitors.

However, currently there are no related reports to difunctional kinaseinhibitors having the biochemical structure of purinyl-N-hydroxylpyrimidine formamide derivative.

SUMMARY OF THE INVENTION

The Invention provides a purinyl-N-hydroxyl pyrimidine formamidederivative having PI3K and HDAC difunctional targets.

Said purinyl-N-hydroxyl pyrimidine formamide derivative, the structureof which is as shown in Formula I:

wherein, X is O or N—R′; R′ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy or an alkylsubstituted by C₁-C₄ hydroxy;

R₁ is C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl;

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen;

R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

As a preferred scheme of the Invention, X is O or N—R′; R′ is —H or analkyl substituted C₁-C₄ hydroxy; R₁ is C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH,halogen, C₃-C₈ cycloalkyl, —NH₂,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₁ is halogen, C₃-C₈ cycloalkyl, —NH₂,

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₂and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen orC₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁ is halogen,

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₂and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen orC₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁ is —Cl,

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₂and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen orC₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy orC₃-C₈ cycloalkyl; X is O or N—R′; R′ is —H or an alkyl substituted byC₁-C₄ hydroxy; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈cycloalkyl; X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄hydroxy; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₂ and R₃ are independently —H, C₁-C₄ alkyl orcyclopentyl alkyl; X is O or N—R′; R′ is —H or an alkyl substituted byC₁-C₄ hydroxy; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ naphthenic base, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ naphthenic base, —NH₂, an alkyl substituted by C₁-C₄hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—NH₂, —COOH, C₁-C₄ alkyl amino or

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₄-R₉ are independently —H, C₁-C₄ alkyl, methoxyl,—NH₂, —COOH, methylamino or

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—OH, —CF₃, halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄hydroxy; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, —CF₃, halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄hydroxy; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; X is O or N—R′; R′ is —H or an alkylsubstituted by C₁-C₄ hydroxy; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆alkenyl,

t-butyloxycarboryl or

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₁₆ is C₁-C₄ alkyl,

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₇ is —NH₂,

—OH or halogen.

More preferably, X is O or N—R′; R′ is —H or an alkyl substituted byC₁-C₄ hydroxy; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,

Most preferably, X is O or N—R′; R′ is —H or hydroxy ethyl; R₁ is —Cl,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or cyclopentyl alkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, methoxy, —NH₂, —COOH, methylamino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, methoxy, —OH, —CF₃, —Cl,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,

Said purinyl-N-hydroxyl pyrimidine formamide derivative, when X is O,the structure of which is as shown in Formula II:

wherein, R₁ is C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen, C₃-C₈cycloalkyl, —NH₂,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl;

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4;

R₁₄ and R₁₅ are independently —H, C₁-C₄, alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen;

R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

As a preferred scheme of the Invention, R₁ is halogen, C₃-C₈ cycloalkyl,—NH₂,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁ is —Cl,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy orC₃-C₈ cycloalkyl; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈cycloalkyl; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₂ and R₃ are independently —H, C₁-C₄ alkyl orcyclopentyl alkyl; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₈cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—NH₂, —COOH, C₁-C₄ alkyl amino or

R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₄-R₉ are independently —H, C₁-C₄ alkyl, methoxy, —NH₂,—COOH, methylamino or

R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

Preferably, R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—OH, —CF₃, halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, —CF₃, halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆alkenyl,

t-butyloxycarboryl or

R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₁₆ is C₁-C₄ alkyl,

R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,

Most preferably, R₁ is —Cl,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or cyclopentyl alkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, methoxy, —NH₂, —COOH, methylamino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, methoxy, —OH, —CF₃, —Cl,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,

Said purinyl-N-hydroxyl pyrimidine formamide derivative, when X is O andR₂ is methyl, the structure of which is as shown in Formula III:

wherein, R₁ is C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen, C₃-C₈cycloalkyl, —NH₂,

R₃ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen or C₃-C₈ cycloalkyl;

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4;

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen;

R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

As a preferred scheme of the Invention, R₁ is halogen, C₃-C₈ cycloalkyl,—NH₂,

R₃ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen or C₃-C₈ cycloalkyl;R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₁ is halogen,

R₃ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen or C₃-C₈ cycloalkyl;R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁ is —Cl,

R₃ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen or C₃-C₈ cycloalkyl;R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₃ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy or C₃-C₈ cycloalkyl; R₁is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₃ is —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁ ishalogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₃ is —H or C₁-C₄ alkyl; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₈cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl,C₁-C₄ alkoxy, —OH, —CF₃, halogen, C₃-C₈ cycloalkyl, —NH₂, an alkylsubstituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁ is —NH₂,

—OH or halogen.

More preferably, R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—NH₂, —COOH, C₁-C₄ alkyl amino or

R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl,C₁-C₄ alkoxy, —OH, —CF₃, halogen, C₃-C₈ cycloalkyl, —NH₂, an alkylsubstituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₄-R₉ are independently —H, C₁-C₄ alkyl, methoxy, —NH₂,—COOH, methylamino or

R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl,C₁-C₄ alkoxy, —OH, —CF₃, halogen, C₃-C₈ cycloalkyl, —NH₂, an alkylsubstituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—OH, —CF₃, halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, —CF₃, halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆alkenyl,

t-butyloxycarboryl or

R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

Preferably, R₁₆ is C₁-C₄ alkyl,

R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₇ is —NH₂,

—OH or halogen.

More preferably, R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,

Most preferably, R₁ is —Cl,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl,methoxy, —NH₂, —COOH, methylamino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, methoxy, —OH, —CF₃, —Cl,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,

Said purinyl-N-hydroxyl pyrimidine formamide derivative, the structuresof which are shown as follows:

The Invention also provides preparation methods of saidpurinyl-N-hydroxyl pyrimidine formamide derivative, the synthetic routeof which is as follows:

Said preparation method of purinyl-N-hydroxyl pyrimidine formamidederivative comprises the following operation steps as:

1) after raw material 1 and ethyl formate are reacted under alkalinecondition for 2 h, adding dimethyl sulfate for reaction for 3-8 h at 50°C. to obtain midbody 2; said alkali is sodium methoxide or sodiumethoxide; the solvent used in the reaction is any one of ethyl alcohol,benzene, methylbenzene or tetrahydrofuran; the reaction temperature ofsaid raw material 1 and ethyl formate is 0-20° C.; and

2) obtaining midbody 3 through refluxing reaction of midbody 2 andcarbamide in ethyl alcohol under the condition of concentratedhydrochloric acid; the dosage of said carbamide is 0.9-1.2 equivalentsof midbody 2; said concentrated hydrochloric acid is of catalyticamount; the solvents used in the reaction are methanol, ethanol andacetonitrile, etc.; the reaction temperature is 60-80° C. and thereaction time is 5-8 h;

3) dehydrogenizing midbody 3 and liquid bromine through refluxing underthe condition of glacial acetic acid; the dosage of said liquid bromineis 1.1-1.5 equivalents of midbody 3; the solvent used in the reaction isan acid solvent with high boiling point, and glacial acetic acid ispreferred; the reaction temperature is 80-120° C.;

4) obtaining midbody 5 through refluxing reaction of midbody 4 andalkali in phosphorus oxychloride; said alkali is any one oftriethylamine, N,N-dimethylaniline, N,N-diethylaniline and DIEA; thedosage of said alkali is 1.5-2 equivalents of midbody 4; the reactiontemperature is 60-100° C. and the reaction time is 2-6 h;

5) obtaining midbody 7 through substitution reaction of raw material 6and R₂I in alkaline condition; the solvent used in the reaction is anyone of acetone, acetonitrile or DMF (N,N-dimethylformamide); the dosageof R₂I is 2-3 equivalents of raw material 6; said alkali is any one ofcesium carbonate, potassium carbonate, NaOH and KOH; the dosage of saidalkali is 1.5-2 equivalents of raw material 6; the reaction temperatureis 25-80° C. and the reaction time is 0.5-2 h;

6) obtaining midbody 8 through the reaction of midbody 7 and

the solvent used in the reaction is an organic alcoholic solventcontaining less than 6 carbons, such as methanol and ethanol; the dosageof

is 1.5-2 equivalents of midbody 7;

7) obtaining midbody 9 by adding DMF for 1-3 h's reaction after 2-3 h'sreaction of midbody 8 and n-butyllithium in THF (tetrahydrofuran); thedosage of said n-butyllithium is 1.6 equivalents of midbody 8; thetemperature for the reaction of midbody 9 and n-butyllithium is −78-−40°C.; the dosage of DMF is 2 equivalents of midbody 8;

8) obtaining midbody 10 through the reaction of midbody 9 and reductant;the solvent used in the reaction is any one of THF, ethanol or methanol;said reductant is LiAlH₄ or NaBH₄, the dosage of which is 2-3equivalents of midbody 9; the reaction temperature is 0-25° C.;

9) obtaining midbody 11 through the reaction of midbody 10 and methanesulfonyl chloride under alkaline condition; the solvent used in thereaction is THF or CH₂Cl₂ (dichloromethane); the alkali is triethylamineor DIEA, the dosage of which is 2-3 equivalents of midbody 10; thedosage of methane sulfonyl chloride is 1.5-2 equivalents of midbody 10;the reaction temperature is 0-25° C.;

10) obtaining midbody 12 through the reaction of midbody 11 and R₃—NH₂;the solvent used in the reaction is ethanol or methanol; the dosage ofR₃—NH₂ is 1.5-2 equivalents of midbody 11; the reaction temperature is0-25° C. and the reaction time is 1-5 h;

11) obtaining midbody 13 through the reaction of midbody 12 and midbody5 under alkaline condition; the solvent used in the reaction is at leastone of acetonitrile, ethyl alcohol or dichloromethane; the dosage ofmidbody 5 is 1.1-1.2 equivalents of midbody 12;

12) obtaining midbody 14 through the coupled reaction of midbody 13 andR₁—B(OH)₂ catalyzed by Pd; the solvent used in the reaction is a mixedsolution of methylbenzene ethyl alcohol and water at a volume ratio of7:3:2; inorganic alkli should be added in the reaction, the dosage ofwhich is 1.5-2 equivalents of midbody 13; said inorganic alkli is anyone of sodium bicarbonate, sodium carbonate, cesium carbonate, NaOH orKOH; said Pd catalyst is any one of tetrakis triphenylphosphinepalladium, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride orpalladium acetate, the dosage of which is catalyze equivalent; thereaction temperature is 80-100° C. and the reaction time is 5-8 h;

13) Obtaining the compound of Formula I through the reaction of midbody14 and hydroxylamine; the solvent used in the reaction is a mixedsolution of methanol and dichloromethane; the concentration of saidhydroxylamine is 4N; the reaction temperature is ambient temperature andthe reaction time is 1-8 h.

Wherein, X is O or N—R′; R′ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy or an alkylsubstituted by C₁-C₄ hydroxy;

R₁ is C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.

The purinyl-N-hydroxyl pyrimidine formamide derivative of the Inventioncomprises its tautomer, stereoisomer and mixtures of all proportions,and also comprises the compound substituted by its isotope.

The Invention also provides a pharmaceutically acceptable salt of saidpurinyl-N-hydroxyl pyrimidine formamide derivative. Wherein, acidaddition salt refers to that the salt is obtained through the reactionof free alkali of the parent compound and inorganic acid or organicacid. Inorganic acid comprises hydrochloric acid, hydrobromic acid,nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid,sulphurous acid and perchloric acid, etc. Organic acid comprises aceticacid, propionic acid, crylic acid, oxalic acid, (D) or (L) malic acid,fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid,methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonicacid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid,p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid,lactic acid, mandelic acid, succinic acid and malonic acid, etc.

The term “pharmaceutically acceptable” used in the Invention refers tothat in the scope of reasonable medical judgment, something applies tocontacting tissues of human and other mammals without any unduetoxicity, stimulus or anaphylactic reaction, and can directly orindirectly provide the compound of the Invention or a prodrug of suchcompound while drugs are administrated to a receptor.

The Invention also provides a pharmaceutically acceptable hydrate ofsaid purinyl-N-hydroxyl pyrimidine formamide derivative. The term“hydrate” refers to a compound of water that is combined with chemometryor non-stoichiometry through the acting force between noncovalentmolecules.

The Invention also provides a pharmaceutically acceptable polymorphicsubstance of said purinyl-N-hydroxyl pyrimidine formamide derivative.The term “polymorphic substance” refers to the solid crystal of acompound or its composite, which can be represented by physical methods,such as X-ray powder diffraction pattern or infrared spectroscopy.

The Invention also provides a pharmaceutically acceptable pharmaceuticalcomposition of said purinyl-N-hydroxyl pyrimidine formamide derivative;such pharmaceutical composition is prepared by the purinyl-N-hydroxylpyrimidine formamide derivative shown in Formulas I-III and its salt orhydrate with pharmaceutically acceptable auxiliary ingredients. Saidauxiliary ingredients are cyclodextrin, arginine or meglumine. Saidcyclodextrin is selected from α-cyclodextrins, β-cyclodextrins,γ-cyclodextrins, (C₁₋₄ alkyl)-α-cyclodextrins, (C₁₋₄alkyl)-β-cyclodextrins, (C₁₋₄ alkyl)-γ-cyclodextrins, (hydroxyl-C₁₋₄alkyl)-α-cyclodextrins, (hydroxyl-C₁₋₄ alkyl)-β-cyclodextrins,(hydroxyl-C₁₋₄ alkyl)-γ-cyclodextrins, (carboxyl-C₁₋₄alkyl)-α-cyclodextrins, (carboxyl-C₁₋₄ alkyl)-β-cyclodextrins,(carboxyl-C₁₋₄ alkyl)-γ-cyclodextrins, carbohydrate ether ofα-cyclodextrins, carbohydrate ether of β-cyclodextrins, carbohydrateether of γ-cyclodextrins, sulfobutyl ether of α-cyclodextrins,sulfobutyl ether of β-cyclodextrins and sulfobutyl ether ofγ-cyclodextrins. Said auxiliary ingredients also comprisepharmaceutically acceptable carrier, adjuvant or agent. Thepharmaceutically acceptable pharmaceutical composition also comprisesion exchanger, aluminium oxide, aluminium stearate, lecithin; the buffersubstance comprises phosphate, glycine, arginine and sorbic acid, etc.

Said pharmaceutical composition can be in either liquid or solid form.Wherein, said liquid form can be the form of aqueous solution; saidsolid form can be the form of powder, particle, tablet or lyophilizedpowder. The pharmaceutical composition also comprises water forinjection, saline solution, glucose aqueous solution, saline forinjection/infusion, glucose for injection/infusion, Ringer's solution orRinger's solution containing lactate.

Uses of the purinyl-N-hydroxyl pyrimidine formamide derivative shown inFormulas I-III and its salt, hydrate or pharmaceutical composition inpreparing PI3K inhibitor.

Uses of the purinyl-N-hydroxyl pyrimidine formamide derivative shown inFormulas I-III and its salt, hydrate or pharmaceutical composition inpreparing HDAC inhibitor.

Uses of the purinyl-N-hydroxyl pyrimidine formamide derivative shown inFormulas I-III and its salt, hydrate or pharmaceutical composition inpreparing antineoplastic drugs.

The Invention also provides uses of the purinyl-N-hydroxyl pyrimidineformamide derivative shown in Formulas I-III and its salt, hydrate orpharmaceutical composition in preparing oral or intravenous injectionpreparations. Said oral or intravenous injection preparations compriseat least one urinyl-N-hydroxyl pyrimidine formamide derivative shown inFormulas I-III and its salt, hydrate or pharmaceutical composition, andany excipients and/or adjuvants.

The purinyl-N-hydroxyl pyrimidine formamide derivative provided in theInvention can be not only a kinase inhibitor with PI3K and HDACdifunctional targets, but also a kinase inhibitor with single PI3K orHDAC functional target, thus providing a new choice for preparingantineoplastic drugs.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiment 1 Synthesisof 2-chloropyrimidine-5-carboxylic acid ethyl ester (midbody 5)

Adding sodium (13.8 g) into the mixture of benzene (300 mL) and ethylalcohol (27 g); slowly adding the mixture of ethyl formate (45 g, 0.61mol) and ethyl 3-ethoxypropionate (44 g, 0.3 mol) into above-mentionedmixture at 0° C. Stirring the obtained reaction mixture for 2 h, thenadding dimethyl sulfate (76 g, 0.61 mol) and stirring for 3 h at 50° C.;filtering the mixture and washing the filtrate with water; separatingand extracting the organic layer, drying it with anhydrous sodiumsulfate, filtering and evaporating it to obtain a residue fordistillation under vacuum condition, then the midbody 2 is obtained;said compound can be directly used in the following steps withoutfurther purification.

Heating up overnight the ethanol (300 mL) mixture of midbody 2 (21.4 g,0.11 mol), carbamide (5.7 g, 0.095 mol), concentrated hydrochloric acidand ethanol (36%-38%, 5 mL) in the state of refluxing; recrystallizingsaid residue in ethanol after evaporation to obtain a colorlessprismatic midbody 3 (7.8 g, 65%).

Heating up the acetic acid solution (55 mL) of midbody 3 (2.5 g, 14.7mmol) and bromine (2.4 g, 15 mmol) for 1.5 h in the state of refluxing;removing said solvent to obtain coarse midbody 4 (3.6 g, 99%), which canbe directly used in the following steps without further purification.

Heating up the mixture of midbody 4 (3.6 g, 21 mmol), phosphorusoxychloride (25 mL) and N,N-dimethylaniline (2.5 mL) for 1.5 h in thestate of refluxing; removing said solvent and then adding ice water (10mL) into said residue; adding said mixture into 2N sodium hydroxide (90mL) and extracting it with ethyl acetate. Evaporating the organic layerfor purification through column chromatography (developing solventpetroleum ether:ethyl acetate=20:1) to obtain midbody 5 (1.2 g, 30%).

Embodiment 22-(((2-chlorine-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)pyrimidine-5-carboxylicacid ethyl ester (midbody 13-1)

Adding midbody 12-1(1-(2-chlorine-9-methyl-6-morpholine-9H-purine-8-yl)-N-methylmethylamine and midbody 5 into acetonitrile mixture as per theequivalent of 1:1 and slowly adding N,N-diisopropylethylamine forovernight reaction; then dissolving out the product from acetonitrile,filtering it to obtain the crude product, then wash it with ethylacetate and dry it to obtain the target midbody 13-1.

Embodiment 3 Synthesis of2-(((2-(6-methoxypyridine-3-yl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-1)

Adding midbody 13-1, 6-methoxypyridine-3-boronic acid and PdCl₂ (dppf)in a reaction flask; vacuumizing it and inletting nitrogen; adding 20 mLsolution of methylbenzene:ethyl alcohol=1:1 and 2 mL Na₂CO₃ aqueoussolution of 2 mol/L in sequence; heating up to 80° C. for overnightreaction. Conducting suction filtration with kieselguhr after completereaction; reducing pressure, removing the solvent and conductingsilicagel column chromatography (developing solvent petroleumether:ethyl acetate=2:1) to obtain the key midbody 14-1.

In the meanwhile, adding methanol solution of potassium hydroxide in themethanol stirring solution of hydroxylamine hydrochloride at 0° C.; thenstirring the mixture for 30 min at 0° C. and allowing it to stay at lowtemperature; separating the obtained sediment and preparing the solutioninto free hydroxylamine.

Adding midbody 14-1 into the free hydroxylamine solution and stirring itfor 1 h; then adding water in the reaction mixture after the reactionand adjusting the PH value to 7-8; filtering it after some solid isdissolved out and cleaning the filter cake with methyl alcohol anddichloromethane to obtain the target compound CLJ-1.

LCMS: 507.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.23 (s, 3H), 3.71-3.77(m, 4H), 3.76 (s, 3H), 3.92 (s, 3H), 4.21-4.27 (br, 4H), 5.17 (s, 2H),6.91 (d, J=8.4 Hz, 1H), 8.58 (d, J=8.4 Hz, 1H), 8.72 (s, 2H), 9.14 (s,1H).

Embodiment 4 Synthesis of 2-(((9-ethyl-2(6-methoxyl3-pyridyl)-6-morpholino-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-2)

The synthesis method is the same as that of Embodiment 3, except thatmethyl iodide is replaced by ethyl iodide in step 5 of the reaction; thesum yield of the final two steps is 41%.

LCMS: 521.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ:1.19 (t, J=7.0 Hz, 3H),3.71-3.82 (m, 4H), 4.21-4.29 (br, 4H), 5.17 (s, 2H), 6.91 (d, 1H, J=8.4Hz), 8.58 (d, 1H, J=8.4 Hz), 8.72 (s, 2H), 9.14 (s, 1H).

Embodiment 5 Synthesis of2-(((9-isopropyl-2-(6-methoxyl-3-pyridyl)-6-morpholino-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-3)

The synthesis method is the same as that of Embodiment 3, except thatmethyl iodide is replaced by 2-iodopropane in step 5 of the reaction;the sum yield of the final two steps is 42%.

LCMS: 534.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ:1.61 (d, 6H, J=6.8 Hz),3.17 (s, 3H), 3.68-3.75 (br, 4H), 3.92 (s, 3H), 4.19-4.28 (br, 4H),4.78-4.87 (m, 1H), 5.18 (s, 2H), 6.91 (d, 1H, J=8.4 Hz), 8.55 (dd, 1H,J=8.4 Hz, J=2.4 Hz), 8.71 (s, 2H), 9.12 (s, 1H).

Embodiment 6 Synthesis of2-(((9-cyclopentyl-2-(6-methoxyl-3-pyridyl)-6-morpholino-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxyl pyrimidine-5-formamide (Compound CLJ-4)

The synthesis method is the same as that of Embodiment 3, except thatmethyl iodide is replaced by iodocyclopentane in step 5 of the reaction;the sum yield of the final two steps is 48%.

LCMS: 561.3 [M+1]+. ¹H-NMR (400 MHz, DMSO-d6) δ: 1.54-1.64 (m, 2H),1.84-1.98 (m, 2H), 2.00-2.09 (m, 2H), 2.30-2.40 (m, 2H), 3.18 (s, 3H),3.66-3.74 (m, 4H), 4.17-4.29 (br, 4H), 4.87-4.97 (m, 1H), 5.20 (s, 2H),6.92 (d, 1H, J=8.8 Hz), 8.52 (dd, 1H, J=8.8, 2.0 Hz), 8.73 (s, 2H), 9.06(s, 1H), 9.10 (d, 1H, J=2.0 Hz), 11.13 (s, 1H).

Embodiment 7 Synthesis ofN-hydroxy-2-(((2-(6-methoxyl-3-pyridyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(ethyl)amino)pyrimidine-5-formamide(Compound CLJ-5)

The synthesis method is the same as that of Embodiment 3, except thatmethylamine is replaced by ethamine in step 9 of the reaction; the sumyield of the final two steps is 33%.

LCMS: 521.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 1.02 (t, 3H, J=4.8 Hz),3.23 (q, 3H, J=4.8 Hz), 3.64-3.71 (m, 4H), 3.76 (s, 3H), 3.92 (s, 3H),4.21-4.29 (br, 4H), 5.17 (s, 2H), 6.91 (d, 1H, J=8.4 Hz), 8.58 (d, 1H,J=8.4 Hz), 8.72 (s, 2H), 9.14 (s, 1H).

Embodiment 8 Synthesis ofN-hydroxy-2-(((2-(6-methoxyl-3-pyridyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(propyl)amino)pyrimidine-5-formamide(Compound CLJ-6)

The synthesis method is the same as that of Embodiment 3, except thatmethylamine is replaced by propylammonia in step 9 of the reaction; thesum yield of the final two steps is 33%.

LCMS: 535.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 0.90 (t, 4.8 Hz, 3H),1.57-1.63 (m, 2H), 3.49 (t, J=4.8 Hz, 2H), 3.71-3.78 (m, 4H), 3.76 (s,3H), 3.92 (s, 3H), 4.21-4.27 (br, 4H), 5.17 (s, 2H), 6.91 (d, J=8.4 Hz,1H), 8.58 (d, J=8.4 Hz, 1H), 8.72 (s, 2H), 9.14 (s, 1H).

Embodiment 9 Synthesis of2-(((2-(p-amino-3-pyridyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-7)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-6-aminopyridineboronic acid; the sum yield of the final two steps is 49%.

LCMS: 492.5 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.14 (s, 3H), 3.65-3.82(m, 7H), 4.12-4.30 (br, 4H), 5.13 (s, 2H), 6.33 (s, 2H), 6.49 (d, J=8.4Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.66 (s, 2H), 8.93 (s, 1H).

Embodiment 10 Synthesis of2-(((2-(4-pyridyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-8)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 4-pyridine boronic acid;the sum yield of the two steps is 30%.

LCMS: 574.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.24 (s, 3H), 3.72-3.80(br, 4H), 3.80 (s, 3H), 3.84 (s, 3H), 4.25 (s, 4H), 5.20 (s, 2H), 8.26(s, 2H), 8.71-8.78 (m, 4H), 9.05 (s, 1H), 11.07 (s, 1H).

Embodiment 11 Synthesis of2-(((2-(3-pyridyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-9)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 3-pyridine boronic acid;the sum yield of the two steps is 33%.

LCMS: 477.5 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.23 (s, 1H), 3.68-3.75(m, 4H), 3.79 (s, 3H), 4.17-4.32 (br, 4H), 7.45-7.51 (m, 1H), 8.60-8.68(m, 2H), 8.72 (s, 2H), 9.53 (s, 1H).

Embodiment 12 Synthesis of2-(((2-(pyrimidine-5-yl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-10)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by pyrimidine-5-boronicacid; the sum yield of the two steps is 35%.

LCMS: 478.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.25 (s, 3H), 3.72-3.78(br, 4H), 3.80 (s, 3H), 4.25-4.32 (br, 4H), 5.19 (s, 2H), 8.72 (s, 2H),9.26 (s, 1H), 9.62 (s, 2H).

Embodiment 13 Synthesis of2-(((2-(2-aminopyrimidine-5-yl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxyl pyrimidine-5-formamide (Compound CLJ-11)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by2-aminopyrimidine-5-boronic acid; the sum yield of the two steps is 42%.

LCMS: 493.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.22 (s, 3H), 3.71-3.82(m, 7H), 4.20-4.28 (br, 4H), 5.16 (s, 2H), 7.03 (s, 2H), 8.73 (s, 2H),9.11 (s, 2H).

Embodiment 14 Synthesis of 2-(((2-(4-aminemethylpyrimidine)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-12)

The synthesis method is the same as that of Embodiment 3, except thatthe 6-methoxypyridine-3-boronic acid is replaced by 4-aminemethylpyrimidine boronic acid; the sum yield of the two steps is 33%.

LCMS: 507.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.92 (s, 3H), 3.22 (s,3H), 3.71-3.80 (m, 7H), 4.20-4.28 (br, 4H), 5.16 (s, 2H), 7.03 (s, 2H),8.73 (s, 2H), 9.11 (s, 2H).

Embodiment 15 Synthesis of2-(((2-(4-methylpyrimidine)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-13)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 4-methoxypyridineboronic acid; the sum yield of the two steps is 32%.

LCMS: 492.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.45 (s, 2H), 3.22 (s,3H), 3.71-3.80 (m, 7H), 4.20-4.28 (br, 4H), 5.16 (s, 2H), 8.73 (s, 2H),9.11 (s, 2H).

Embodiment 16 Synthesis of2-(((2-(quinoline-3-yl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-14)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by quinolone-3-boronicacid; the sum yield of the two steps is 37%.

LCMS: 527.5 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.21 (s, 3H), 3.76 (s,4H), 3.82 (s, 3H), 4.30 (s, 4H), 5.19 (s, 2H), 7.65 (t, 1H, J=7.6 Hz),7.80 (t, 1H, J=7.6 Hz), 8.07 (d, 1H, J=8.4 Hz), 8.16 (d, 1H, J=8.0 Hz),8.71 (s, 2H), 9.21 (s, 1H), 9.87 (s, 1H).

Embodiment 17 Synthesis of2-(((2-(1H-indazole-5-yl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-15)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 1H-indazole-5-boronicacid; the sum yield of the two steps is 45%.

LCMS: 516.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.24 (s, 3H), 3.75 (s,4H), 3.84 (s, 3H), 4.18-4.36 (br, 4H), 5.21 (s, 2H), 7.46 (s, 1H), 7.65(s, 1H), 8.21 (s, 1H), 8.74 (s, 2H), 8.91 (s, 1H), 13.21 (s, 1H).

Embodiment 18 Synthesis ofN-hydroxy-2-(((2-(1H-indazole-5-yl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(propyl)amino)pyrimidine-5-formamide(Compound CLJ-16)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 1H-indazole-5-boronicacid and meanwhile methylamine is replaced by propylamine in step 9 ofthe reaction; the sum yield of the final two steps is 27%.

LCMS: 544.3[M+1]⁺. ¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (t, 4.8 Hz, 3H),1.57-1.64 (m, 2H), 2.24 (s, 1H), 3.49 (t, 2H, J=4.8 Hz), 3.73-3.84 (m,4H), 3.77 (s, 3H), 4.25 (s, 4H), 5.20 (s, 2H), 7.77 (s, 1H), 8.12 (s,1H), 8.24 (s, 2H), 8.64 (s, 2H).

Embodiment 19 Synthesis ofN-hydroxy-2-(((2-(1H-indazole-5-yl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(butyl)amino)pyrimidine-5-formamide(Compound CLJ-17)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 1H-indazole-5-boronicacid and meanwhile methylamine is replaced by butyl in step 9 of thereaction; the sum yield of the final two steps is 42%.

LCMS: 558.3[M+1]⁺. ¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (t, 3H, J=4.8 Hz),1.37-1.45 (m, 2H), 1.49-1.54 (m, 2H), 2.24 (s, 1H), 3.49 (t, 2H, J=4.8Hz), 3.73-3.78 (m, 4H), 3.77 (s, 3H), 4.25 (s, 4H), 5.20 (s, 2H), 7.77(s, 1H), 8.12 (s, 1H), 8.24 (s, 2H), 8.64 (s, 2H).

Embodiment 20 Synthesis of2-(((2-(2-thienyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-18)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by thiophene-2-boronicacid; the sum yield of the two steps is 28%.

LCMS: 481.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.18 (s, 3H), 3.72 (s,7H), 4.22 (s, 4H), 5.15 (s, 2H), 7.54-7.61 (m, 1H), 7.80 (d, 1H, J=4.8Hz), 8.23 (s, 1H), 8.68 (s, 2H).

Embodiment 21 Synthesis of2-(((2-(3-methyl-2-thienyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-19)

The operation is the same as that of Embodiment 3, except that the6-methoxypyridine-3-boronic acid is replaced by(3-methyl-2-thienyl)boronic acid in step 12; the sum yield of the finaltwo steps is 53%.

LCMS: 496.1[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.34 (s, 3H), 3.16 (s,3H), 3.73-3.79 (br, 7H), 4.22 (s, 4H), 5.18 (s, 2H), 7.82 (d, 1H, J=4.4Hz), 8.20 (s, 1H), 8.72 (s, 2H).

Embodiment 22 Synthesis of2-(((2-(5-carboxyl-2-thienyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-20)

The operation is the same as that of Embodiment 3, except that the6-methoxypyridine-3-boronic acid is replaced by(5-carboxyl-2-thienyl)boronic acid in step 12; the sum yield of thefinal two steps is 48%.

LCMS: 526.1[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.16 (s, 3H), 3.72-3.82(br, 7H), 4.26 (s, 4H), 5.22 (s, 2H), 7.88 (d, 1H, J=4.4 Hz), 8.25 (s,1H), 8.73 (s, 2H).

Embodiment 23 Synthesis of2-(((2-(5-n-butyl-2-thienyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-21)

The operation is the same as that of Embodiment 3, except that the6-methoxypyridine-3-boronic acid is replaced by(5-carboxyl-2-thienyl)boronic acid in step 12; the sum yield of thefinal two steps is 48%.

LCMS: 538.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 0.9 (t, 3H, J=7.2 Hz),1.33-1.51 (m, 4H), 2.36 (t, 2H, J=7.6 Hz), 3.18 (s, 3H), 3.71 (s, 7H),4.16-4.30 (br, 4H), 5.16 (s, 2H), 7.15 (t, 1H, J=3.6 Hz), 7.58 (d, 1H,J=4.4 Hz), 8.72 (s, 2H).

Embodiment 24 Synthesis of2-(((2-(3-thienyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-22)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by pyrrole-2-boronic acid;the sum yield of the two steps is 43%.

LCMS: 482.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.19 (s, 3H), 3.71 (s,7H), 4.12-4.30 (br, 4H), 5.15 (s, 2H), 7.13 (t, 1H, J=3.2 Hz), 7.61 (d,1H, J=4.4 Hz), 7.83 (d, 1H, J=2.8 Hz), 8.70 (s, 2H).

Embodiment 25 Synthesis of2-(((2-(3-methyl-3-thienyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-23)

The operation is the same as that of Embodiment 3, except that the6-methoxypyridine-3-boronic acid is replaced by(3-methyl-3-thienyl)boronic acid in step 12; the sum yield of the finaltwo steps is 56%.

LCMS: 496.1[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.38 (s, 3H), 3.16 (s,3H), 3.71-3.77 (br, 7H), 4.18-4.32 (br, 4H), 5.17 (s, 2H), 7.12 (t, 1H,J=3.2 Hz), 7.58 (d, 1H, J=4.4 Hz), 8.72 (s, 2H).

Embodiment 26 Synthesis of2-(((2-(1H-2-pyrrolyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-24)

The operation is the same as that of Embodiment 3, except that the6-methoxypyridine-3-boronic acid is replaced by(1(1H)-2-pyrrolyl)boronic acid in step 12; the sum yield of the finaltwo steps is 49%.

LCMS: 565.1[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.16 (s, 3H), 3.71 (s,7H), 4.22-4.28 (br, 4H), 5.18 (s, 2H), 7.54-7.61 (m, 1H), 7.82 (d, 1H,J=4.4 Hz), 8.17 (s, 1H), 8.72 (s, 2H), 11.43 (s, 1H).

Embodiment 27 Synthesis of2-(((1-(2-(dimethylamino)ethyl)-1H-4-pyrazolyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-25)

The operation is the same as that of Embodiment 3, except that the6-methoxypyridine-3-boronic acid is replaced by(1-(2-(dimethylamino)ethyl)-1H-4-pyrazolyl)boronic acid in step 12; thesum yield of the final two steps is 52%.

LCMS: 537.1[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.88 (s, 6H), 3.16 (s,3H), 3.71-3.76 (m, 9H), 4.22-4.26 (br, 4H), 5.18 (s, 2H), 5.46 (t, 2H,J=7.6 Hz), 7.94 (s, 1H), 7.97 (s, 1H), 8.70 (s, 2H).

Embodiment 28 Synthesis of2-(((2-(2-furyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-26)

The operation is the same as that of Embodiment 3, except that the6-methoxypyridine-3-boronic acid is replaced by 2-furan boronic acid instep 12; the sum yield of the final two steps is 46%.

LCMS: 466.1[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.21 (s, 3H), 3.63-3.77(m, 7H), 4.11-4.29 (br, 4H), 5.16 (s, 2H), 6.61 (s, 1H), 7.14 (d, 1H,J=2.8 Hz), 7.80 (s, 1H), 8.72 (s, 2H).

Embodiment 29 Synthesis of2-(((2-(3-hydroxyphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-27)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 3-hydroxy phenylboronicacid; the sum yield of the two steps is 37%.

LCMS: 492.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.22 (s, 3H), 3.73-3.79(br, 4H), 3.75 (s, 3H), 4.23-4.29 (br, 4H), 5.18 (s, 2H), 6.82 (s, 1H),7.24-7.28 (m, 1H), 7.84-7.92 (m, 2H), 8.73 (s, 2H).

Embodiment 30 Synthesis of2-(((2-(4-hydroxyphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-28)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boric acid is replaced by p-hydroxy phenylboronicacid; the sum yield of the two steps is 53%.

LCMS: 492.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO) δ: 3.18 (s, 3H), 3.66-3.74 (m,4H), 3.77 (s, 3H), 4.27 (s, 4H), 5.16 (s, 2H), 7.82 (d, 2H, J=8.8 Hz),8.58 (d, 2H, J=8.8 Hz), 8.64 (s, 2H).

Embodiment 31 Synthesis of2-(((2-(4-methoxyphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-29)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boric acid is replaced by p-methoxy phenylboronicacid; the sum yield of the two steps is 22%.

LCMS: 506.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.23 (s, 3H), 3.72-3.78(m, 4H), 3.75 (s, 3H), 3.81 (s, 3H), 4.22-4.28 (br, 4H), 5.17 (s, 2H),7.01 (d, 2H, J=8.8 Hz), 8.33 (d, 2H, J=8.8 Hz), 8.72 (s, 2H), 9.03 (s,1H), 11.09 (s, 1H).

Embodiment 32 Synthesis of2-((9-ethyl-2(4-methoxyphenyl)-6-morpholino-9H-purine-8-yl)methyl)(methyl)amino-N-hydroxylpyrimidine-5-formamide (Compound CLJ-30)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boric acid is replaced by p-methoxy phenylboronicacid and meanwhile methyl iodide is replaced by ethyl iodide in step 5of the reaction; the sum yield of the final two steps is 46%.

LCMS: 520.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 1.29 (t, 2H, J=7.0 Hz),3.64-3.72 (m, 4H), 3.75 (s, 3H), 3.81 (s, 3H), 4.12 (q, 3H, J=7.2 Hz),4.22-4.30 (br, 4H), 5.17 (s, 2H), 7.01 (d, 2H, J=8.8 Hz), 8.33 (d, 2H,J=8.8 Hz), 8.72 (s, 2H), 9.03 (s, 1H), 11.10 (s, 1H).

Embodiment 33 Synthesis of2-(((9-isopropyl-2-(6-metoxybenzene)-6-morpholino-9H-purine-8-yl)methyl)(methyl)amino-N-hydroxylpyrimidine-5-formamide (Compound CLJ-31)

The synthesis method is the same as that of Embodiment 3, except thatmethyl iodide is replaced by 2-iodopropane in step 5 and6-methoxy-3-pyridine boronic acid is replaced by 6-methoxy boronic acidin step 12 of the reaction; the sum yield of the final two steps is 38%.

LCMS: 534.3 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ:1.62 (d, 6H, J=6.4 Hz),3.19 (s, 1H), 3.67-3.75 (m, 4H), 3.81 (s, 3H), 4.18-4.28 (br, 4H),4.78-4.84 (m, 1H), 5.18 (s, 2H), 7.01 (d, 2H, J=8.8 Hz), 8.30 (d, 2H,J=8.8 Hz), 8.73 (s, 2H), 9.05 (s, 1H), 11.06 (s, 1H).

Embodiment 34 Synthesis of2-(((9-cyclopentyl-2(4-methoxyphenyl)-6-morpholine-9H-purine-8-yl)methyl)(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-32)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-methoxy phenylboronicacid and meanwhile methyl iodide is replaced by cyclopentane in step 5of the reaction; the sum yield of the final two steps is 39%.

LCMS: 562.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 1.56-1.64 (m, 4H),1.83-1.92 (m, 4H), 3.23 (s, 3H), 3.61-3.70 (m, 2H), 3.72-3.76 (m, 4H),3.81 (s, 3H), 4.22-4.30 (br, 4H), 5.17 (s, 2H), 7.01 (d, 2H, J=8.8 Hz),8.33 (d, 2H, J=8.8 Hz), 8.72 (s, 2H), 9.03 (s, 1H), 11.09 (s, 1H).

Embodiment 35 Synthesis ofN-hydroxy-2-(((2-(4-methoxyphenyl)-6-morpholino-9-butyl-9H-purine-8-yl)methyl)(methyl)amino)pyrimidine-5-formamide(Compound CLJ-33)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-methoxy phenylboronicacid and meanwhile methyl iodide is replaced by butyl iodide in step 5of the reaction; the sum yield of the final two steps is 36%.

LCMS: 548.4[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 0.90 (t, 3H, J=5.2 Hz),1.29 (t, 2H, J=7.0 Hz), 1.97-2.04 (m, 2H), 3.68-3.72 (m, 4H), 3.75 (s,3H), 3.81 (s, 3H), 4.12 (q, 3H, J=7.0 Hz), 4.22-4.28 (br, 4H), 5.17 (s,2H), 7.01 (d, 2H, J=8.8 Hz), 8.33 (d, 2H, J=8.8 Hz), 8.72 (s, 2H), 9.03(s, 1H), 11.10 (s, 1H).

Embodiment 36 Synthesis ofN-hydroxy-2-(((2-(4-methoxyphenyl)-9-methyl-6-morpholine-9H-purine-8-yl)methyl)amino)pyrimidine-5-formamide(Compound CLJ-34)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-methoxy phenylboronicacid and meanwhile methylamine is replaced by ammonia in step 9 of thereaction; the sum yield of the final two steps is 37%.

LCMS: 492.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.68-3.72 (m, 4H), 3.75(s, 3H), 3.81 (s, 3H), 4.22-4.30 (br, 4H), 5.17 (s, 2H), 7.01 (d, 2H,J=8.8 Hz), 8.33 (d, 2H, J=8.8 Hz), 8.72 (s, 2H), 9.03 (s, 1H), 10.01 (s,1H), 11.09 (s, 1H).

Embodiment 37 Synthesis of2-(((2-(3,4,5-trimetoxyphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-35)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by3,4,5-trimetoxyphenylboronic acid; the sum yield of the two steps is29%.

LCMS: 551.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.21 (s, 3H), 3.69-3.76(br, 7H), 3.77 (s, 3H), 3.87 (s, 6H), 4.18-4.31 (br, 4H), 5.16 (s, 2H),7.72 (s, 2H), 8.70 (s, 2H).

Embodiment 38 Synthesis of2-(((2-(benzo[d][1,3]dioxole-5-yl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-36)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by benzo 1,3dioxolane-5-boronic acid; the sum yield of the two steps is 45%.

LCMS: 520.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.21 (s, 3H), 3.64-3.72(m, 4H), 3.74 (s, 3H), 4.22 (s, 4H), 5.16 (s, 2H), 6.08 (s, 2H), 6.90(d, 1H, J=8.4 Hz), 7.87 (s, 1H), 7.99 (d, 1H, J=8.4 Hz), 8.71 (d, 2H,J=4.4 Hz).

Embodiment 39 Synthesis of 2-(((2-(benzo[d][1.4]dioxy heterocyclichexylene-6-yl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-37)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by benzo 1,4dioxane-6-boronic acid in step 12; the sum yield of the two steps is41%.

LCMS: 533.7 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.22 (s, 3H), 3.70 (s,4H), 3.74 (s, 3H), 4.15-4.25 (br, 4H), 4.28 (s, 2H), 5.17 (s, 2H), 6.92(d, 1H, J=8.4 Hz), 7.80-7.90 (m, 2H), 8.72 (s, 2H), 9.04 (s, 1H), 11.11(s, 1H).

Embodiment 40 Synthesis of2-(((2-(2-methoxy-5-trifluoromethylphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-38)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by2-methoxy-5-trifluoromethyl phenylboronic acid; the sum yield of the twosteps is 31%.

LCMS: 574.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.22 (s, 3H), 3.58-3.64(m, 4H), 3.70 (s, 3H), 3.84 (s, 3H), 4.15 (s, 4H), 5.18 (s, 2H), 7.30(d, 1H, J=8.8 Hz), 7.76 (d, 1H, J=8.4 Hz), 7.80 (s, 1H), 8.71 (s, 2H).

Embodiment 41 Synthesis of2-(((2-(2-(3-(1-hydroxyethyl)2-phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-39)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 3-(1-hydroxyethyl)phenylboronic acid; the sum yield of the two steps is 33%.

LCMS: 536.3[M+1]⁺. ¹H-NMR (400 MHz, CDCl₃) δ: 1.59 (s, 3H), 2.11 (s,1H), 2.17 (s, 1H), 3.16 (s, 3H), 3.64-3.72 (m, 4H), 3.80 (s, 4H), 3.93(s, 3H), 4.51 (s, 1H), 4.58 (s, 1H), 4.71 (s, 1H), 6.86 (s, 1H), 7.36(s, 1H), 7.50 (s, 1H), 7.81 (s, 1H), 8.03 (s, 1H), 8.48 (s, 2H).

Embodiment 42 Synthesis of2-(((2-(3-(hydroxymethyl)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-40)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 3-hydroxymethylphenylboronic acid; the sum yield of the two steps is 36%.

LCMS: 506.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.17 (d, 2H, J=9.2 Hz),3.14 (s, 3H), 3.73-3.79 (br, 4H), 3.91 (s, 3H), 4.25 (s, 4H), 4.59 (d,4H, J=13.2 Hz), 6.86 (s, 1H), 7.49 (d, 2H, J=14.0 Hz), 7.80 (s, 1H),8.03 (s, 1H), 8.48 (s, 2H).

Embodiment 43 Synthesis of2-(((2-(3-(2-hydroxylethyoxyl)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-41)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by (3-(2-hydroxylethyoxyl)phenylboronic acid; the sum yield of the two steps is 32%.

LCMS: 536.3[M+1]⁺. ¹H-NMR (400 MHz, CDCl₃) δ: 3.23 (s, 3H), 3.73-3.79(m, 6H), 3.75 (s, 3H), 4.23-4.29 (br, 4H), 4.33 (m, 2H), 5.18 (s, 2H),6.82 (s, 1H), 7.24-7.28 (m, 1H), 7.84-7.92 (m, 2H), 8.73 (s, 2H).

Embodiment 44 Synthesis of2-(((2-(4-((2-hydroxycaproyl)sulfydryl)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-42)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by(4-((2-hydroxycaproyl)sulfydryl)phenyl)boronic acid in step 12; the sumyield of the final two steps is 42%.

LCMS: 536.3[M+1]⁺. ¹HNMR (400 MHz, DMSO-d6) δ: 3.22 (s, 3H), 3.72-3.78(m, 6H), 3.76 (s, 3H), 4.23-4.31 (br, 4H), 4.33 (m, 2H), 5.16 (s, 2H),5.56 (s, 1H), 6.82 (d, 2H, J=8.8 Hz), 8.18 (d, 2H, J=8.8 Hz), 8.73 (s,2H), 9.01 (s, 1H), 11.03 (s, 1H).

Embodiment 45 Synthesis of2-(((2-(4-isobutoxyphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-43)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by isobutoxy phenylboronicacid in step 12; the sum yield of the final two steps is 49%.

LCMS: 548.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 0.91 (s, 6H), 1.88 (m,1H), 3.22 (s, 3H), 3.71-3.79 (m, 4H), 3.75 (s, 3H), 3.88 (m, 2H),4.22-4.28 (br, 4H), 5.16 (s, 2H), 7.11 (d, 2H, J=8.8 Hz), 8.34 (d, 2H,J=8.8 Hz), 8.73 (s, 2H), 9.03 (s, 1H), 11.09 (s, 1H).

Embodiment 46 Synthesis of2-(((2-p-aminophenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-44)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-amino phenylboronicacid; the sum yield of the two steps is 34%.

LCMS: 491.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.17 (s, 3H), 3.64-3.72(m, 7H), 4.20 (s, 4H), 5.13 (s, 2H), 5.44 (s, 2H), 6.59 (d, 2H, J=8.4Hz), 8.09 (d, 2H, J=8.4 Hz), 8.70 (s, 2H).

Embodiment 47 Synthesis ofN-hydroxy-2-(((2-(4-aminophenyl)-6-morpholino-9-propyl-9H-purine-8-yl)methyl)(methyl)amino)pyrimidine-5-formamide(Compound CLJ-45)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-amino phenylboronicacid and meanwhile methyl iodide is replaced by iodopropane in step 5 ofthe reaction; the sum yield of the final two steps is 42%.

LCMS: 519.4[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 0.9 (t, J=5.2 Hz, 3H),1.74-1.81 (m, 2H), 3.12 (s, 3H), 3.74-3.80 (br, 4H), 4.16 (t, 2H, J=10.0Hz), 4.27 (s, 4H), 5.16 (s, 2H), 7.03 (s, 2H), 7.82 (d, 2H, J=8.4 Hz),8.58 (d, 2H, J=8.4 Hz), 8.64 (s, 2H).

Embodiment 48 Synthesis of 2-(((2-(4-N,N-(hydroxymethyl)dimethylphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-46)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 4-N,N-dimethylphenylboronic acid; the sum yield of the two steps is 50%.

LCMS: 519.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.06 (s, 6H), 3.16 (s,3H), 3.74-3.80 (br, 4H), 3.77 (s, 3H), 4.27 (s, 4H), 5.16 (s, 2H), 7.82(d, 2H, J=8.4 Hz), 8.58 (d, 2H, J=8.4 Hz), 8.64 (s, 2H).

Embodiment 49 Synthesis of N-hydroxy-2-(((2-(4-methylaminophenyl)-9-methyl-6-morpholine-9H-purine-8-yl)methyl)(butyl)amino)pyrimidine-5-formamide(Compound CLJ-47)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-methylamino boronicacid and meanwhile methylamine is replaced by butyl amine in step 9 ofthe reaction; the sum yield of the final two steps is 21%.

LCMS: 547.3[M+1]⁺. ¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (t, 3H, J=4.8 Hz),1.37-1.43 (m, 2H), 1.49-1.58 (m, 2H), 2.68 (s, 3H), 3.49 (t, 2H, J=4.8Hz), 3.73-3.84 (m, 4H), 3.77 (s, 3H), 4.25 (s, 4H), 5.20 (s, 2H), 7.77(s, 1H), 8.12 (d, 2H, J=8.4 Hz), 8.24 (d, 2H, J=8.4 Hz), 8.64 (s, 2H).

Embodiment 50 Synthesis of 2-(((9-methyl-2(p-aminoethylbenzene)-6-morpholino-9H-purine-8-yl)methyl)(methyl)amino-N-hydroxylpyrimidine-5-formamide (Compound CLJ-48)

The synthesis method is the same as that of Embodiment 3, except that6-methoxy-3-pyridine boronic acid is replaced by p-aminoethylphenylboronic acid in step 12 of the reaction; the sum yield of thefinal two steps is 37%.

LCMS: 519.3 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 1.18 (t, 3H, J=7.2 Hz),3.05-3.12 (m, 2H), 3.21 (s, 3H), 3.67-3.75 (br, 7H), 4.15-4.26 (br, 4H),5.16 (s, 2H), 5.53-5.66 (t, 1H, J=5.2 Hz), 6.59 (d, 2H, J=8.8 Hz), 8.14(d, 2H, J=8.8 Hz), 8.72 (s, 2H), 9.05 (s, 1H), 11.11 (s, 1H).

Embodiment 51 Synthesis of 2-(((9-methyl-2(p-N,N-diisopentenylphenylamino)-6-morpholino-9H-purine-8-yl)methyl)(methyl)amino-N-hydroxylpyrimidine-5-formamide (Compound CLJ-49)

The synthesis method is the same as that of Embodiment 3, except that6-methoxy-3-pyridine boronic acid is replaced by 4-N,N-diisopentenylphenylboronic acid in step 12 of the reaction; the sum yield of thefinal two steps is 38%.

LCMS: 627.5 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 1.70 (d, J=3.6 Hz,12H), 3.21 (s, 3H), 3.67-3.76 (br, 7H), 3.92 (d, J=5.6 Hz, 4H), 414-4.26(br, 4H), 5.16 (s, 4H), 6.68 (d, J=8.8 Hz, 2H), 8.18 (d, J=8.8 Hz, 2H),8.73 (s, 2H), 9.05 (s, 1H), 11.10 (s, 1H).

Embodiment 52 Synthesis of 2-(((2-(3-(2-chloroethylsulfonamide)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-50)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by (3-(2-chloroethylsulfonamido)phenyl)boronic acid in step 12; the sum yield of the finaltwo steps is 38%.

LCMS: 617.4 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.22 (s, 3H), 3.73-3.78(m, 6H), 3.79 (s, 3H), 3.94 (m, 2H), 4.23-4.31 (br, 4H), 5.16 (s, 2H),6.84 (s, 1H), 7.24-7.28 (m, 1H), 7.82-7.92 (m, 2H), 8.73 (s, 2H), 9.43(s, 1H).

Embodiment 53 Synthesis of 2-(((2-(3-(2-chloropropylsulfonamide)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-51)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by (4-(2-chloropropylsulfonamido)phenyl)boronic acid in step 12; the sum yield of the finaltwo steps is 42%.

LCMS: 631.2 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.28 (m, 2H), 3.10 (t,2H, J=2.4 Hz), 3.23 (s, 3H), 3.70-3.78 (m, 6H), 3.80 (s, 1H), 3.98 (m,2H), 4.21-4.31 (br, 4H), 5.18 (s, 2H), 7.24 (d, 2H, J=8.4 Hz), 7.82 (d,2H, J=8.4 Hz), 8.78 (s, 2H), 9.03 (s, 1H), 9.44 (s, 1H), 11.09 (s, 1H).

Embodiment 54 Synthesis of 2-(((2-(4-t-butyloxycarborylamino)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-52)

The operation is the same as that of Embodiment 3, except that the6-methoxypyridine-3-boronic acid is replaced by (4-aminot-butyloxycarboryl phenylboronic acid in step 12; the sum yield of thefinal two steps is 32%.

LCMS: 591.3 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 1.34 (s, 9H), 3.18 (s,3H), 3.64-3.72 (m, 7H), 4.22 (s, 4H), 5.16 (s, 2H), 7.11 (d, 2H, J=8.4Hz), 8.09 (d, 2H, J=8.4 Hz), 8.81 (s, 2H), 9.41 (s, 1H).

Embodiment 55 Synthesis of2-(((2-(2-methanesulfonamide)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-53)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boric acid is replaced by 2-methanesulfonamidephenylboronic acid in step 12; the sum yield of the final two steps is39%.

LCMS: 569.2 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.21 (s, 3H), 3.25 (s,3H), 3.63-3.72 (m, 7H), 4.42-4.46 (br, 4H), 5.16 (s, 2H), 7.01-7.10 (m,2H), 7.28 (s, 1H), 7.60 (s, 1H), 8.70 (s, 2H).

Embodiment 56 Synthesis of2-(((2-(-4-chlorine-3-trifluoromethylphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-54)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by4-chlorine-3-trifluoromethyl phenylboronic acid; the sum yield of thetwo steps is 25%.

LCMS: 578.2[M+1]⁺. ¹H-NMR (400 MHz, CDCl₃) δ: 3.30 (s, 3H), 3.81 (s,3H), 3.87 (s, 4H), 4.35 (s, 4H), 7.55 (d, 1H, J=8.4 Hz), 8.54 (d, 1H,J=8.4 Hz), 8.77 (s, 2H), 8.95 (s, 1H).

Embodiment 57 Synthesis of2-(((2-p-trifluoromethylphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-55)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-trifluoromethylphenylboronic acid; the sum yield of the two steps is 41%.

LCMS: 544.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.16 (s, 3H), 3.70-3.76(br, 4H), 3.77 (s, 3H), 4.27 (s, 4H), 5.16 (s, 2H), 7.82 (d, 2H, J=8.4Hz), 8.58 (d, 2H, J=8.4 Hz), 8.64 (s, 2H).

Embodiment 58 Synthesis of2-(((2-3,5-ditrifluoromethylphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-56)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 3,5-ditrifluoromethylphenylboronic acid; the sum yield of the two steps is 40%.

LCMS: 612.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.25 (s, 3H), 3.63-3.74(m, 4H), 3.82 (s, 3H), 4.24-2.30 (br, 4H), 5.20 (s, 2H), 8.21 (s, 1H),8.72 (s, 2H), 8.90 (s, 2H).

Embodiment 59 Synthesis of2-(((2-(4-methylsulphonylphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-57)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-methylsulphonylphenylboronic acid; the sum yield of the two steps is 21%.

LCMS: 554.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.25 (s, 6H), 3.73 (s,4H), 3.79 (s, 3H), 4.25 (s, 4H), 5.20 (s, 2H), 8.02 (d, 2H, J=7.8 Hz),8.61 (d, 2H, J=8.0 Hz), 8.73 (s, 2H).

Embodiment 60 Synthesis of2-(((2-(4-(N-(3-chloropropyl)sulfonamide)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-58)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by(4-(N-(3-chloropropyl)sulfonamide)phenyl)boronic acid in step 12; thesum yield of the final two steps is 41%.

LCMS: 631.3 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.21 (m, 2H), 3.12 (t,2H, J=2.0 Hz), 3.22 (s, 3H), 3.70-3.78 (m, 6H), 3.82 (s, 1H), 3.98 (m,2H), 4.21-4.29 (br, 4H), 5.16 (s, 2H), 7.26 (d, 2H, J=8.4 Hz), 7.80 (d,2H, J=8.4 Hz), 8.70 (s, 2H), 9.01 (s, 1H), 9.44 (s, 1H), 11.08 (s, 1H).

Embodiment 61 Synthesis of2-(((2-(3-(N-(hydroxymethyl)sulfonamide)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-59)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by(3-(N-(hydroxymethyl)sulfonyl)phenyl)boronic acid in step 12; the sumyield of the final two steps is 48%.

LCMS: 584.2 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.18 (s, 3H), 3.73-3.79(br, 4H), 3.75 (s, 3H), 4.20-4.28 (br, 4H), 5.16 (s, 2H), 5.48 (m, 2H),6.81 (s, 1H), 7.21-7.27 (m, 2H), 7.84-7.88 (m, 1H), 8.70 (s, 2H), 9.03(s, 1H), 10.08 (s, 1H).

Embodiment 62 Synthesis of 2-(((2-(p-methylbenzene)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-60)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-methyl phenylboronicacid; the sum yield of the final two steps is 59%.

LCMS: 490.5 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.36 (s, 3H), 3.21 (s,3H), 3.72 (s, 4H), 3.75 (s, 3H), 4.18-4.30 (br, 4H), 5.17 (s, 2H), 7.27(d, 2H, J=8.0 Hz), 8.29 (d, 2H, J=8.0 Hz), 8.71 (s, 2H).

Embodiment 63 Synthesis of2-(((2-(4-ethylphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-61)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 4-ethyl phenylboronicacid in step 12; the sum yield of the final two steps is 44%.

LCMS: 503.8[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 1.21 (t, 3H, J=7.2 Hz),2.66 (q, 2H, J=7.2 Hz), 3.23 (s, 3H), 3.76 (s, 4H), 4.23 (s, 4H), 5.18(s, 2H), 7.30 (d, 2H, J=7.2 Hz), 8.30 (d, 2H, J=7.6 Hz), 8.73 (s, 2H),9.06 (s, 1H), 11.12 (s, 1H).

Embodiment 64 Synthesis of2-(((2-(4-propylphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-62)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 4-propyl phenylboronicacid in step 12; the sum yield of the final two steps is 42%.

LCMS: 517.0 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 0.92 (t, 3H, J=7.2 Hz),1.62 (m, 2H), 2.60 (t, 2H, J=7.6 Hz), 3.22 (s, 3H), 3.72 (m, 4H), 3.76(s, 3H), 4.23 (m, 4H), 5.18 (s, 2H), 7.28 (d, 2H, J=8.0 Hz), 8.29 (d,2H, J=8.0 Hz), 8.72 (s, 2H).

Embodiment 65 Synthesis of2-(((9-methyl-2(4-t-butylphenyl)-6-morpholino-9H-purine-8-yl)methyl)(methyl)amino-N-hydroxylpyrimidine-5-formamide (Compound CLJ-63)

The synthesis method is the same as that of Embodiment 3, except that6-methoxy-3-pyridine boronic acid is replaced by p-tertiary butylboronic acid in step 12 of the reaction; the sum yield of the final twosteps is 42%.

LCMS: 532.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 1.32 (s, 9H), 3.23 (s,3H), 3.67-3.75 (m, 4H), 3.76 (s, 3H), 4.17-4.29 (br, 4H), 5.18 (s, 2H),7.48 (d, 2H, J=8.4 Hz), 8.29 (d, 2H, J=8.4 Hz), 8.73 (s, 2H), 9.06 (s,1H), 11.12 (s, 1H).

Embodiment 66 Synthesis of2-(((2-(3-carbamoylphenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-64)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 3-carbamoylphenylboronic acid in step 12; the sum yield of the final two steps is47%.

LCMS: 519.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.23 (s, 3H), 3.73-3.79(br, 4H), 3.75 (s, 3H), 4.23-4.29 (br, 4H), 5.16 (s, 2H), 6.76 (s, 1H),7.24-7.32 (m, 2H), 7.84-7.88 (m, 1H), 8.70 (s, 2H), 8.88 (s, 2H), 9.03(s, 1H), 11.09 (s, H).

Embodiment 67 Synthesis of2-(((2-(3-(N-(hydroxyethyl)acylamino)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-65)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by(3-(N-(hydroxyethyl)acylamino)phenyl)boronic acid in step 12; the sumyield of the final two steps is 47%.

LCMS: 563.2 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.18 (s, 3H), 3.30 (m,2H), 3.60-3.65 (m, 2H), 3.71-3.77 (br, 4H), 3.76 (s, 3H), 4.20-4.28 (br,4H), 5.16 (s, 2H), 6.88 (s, 1H), 7.20-7.26 (m, 1H), 7.84-7.92 (m, 2H),8.72 (s, 2H), 8.88 (s, 1H), 9.03 (s, 1H), 9.44 (s, 1H), 11.09 (s, 1H).

Embodiment 68 Synthesis of2-(((2-(3-(4-(hydroxymethyl)piperazine-1-carbonyl)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-66)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by(3-(4-(hydroxymethyl)piperazine-1-carbonyl)phenyl)boronic acid in step12; the sum yield of the final two steps is 49%.

LCMS: 618.3 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.55-2.63 (br, 4H),3.23 (s, 3H), 3.44-3.52 (m, 4H), 3.72-3.78 (br, 4H), 3.76 (s, 3H),4.22-4.28 (br, 4H), 4.60 (s, 2H), 5.16 (s, 2H), 6.83 (s, 1H), 7.06 (s,1H), 7.24-728 (m, 2H), 7.84-7.90 (m, 1H), 8.72 (s, 2H), 9.03 (s, 1H),11.09 (s, 1H).

Embodiment 69 Synthesis of2-(((2-(4-((4-morpholinylmethy)phenyl)-9-methyl-6-morpholine-9H-purine-8-yl))methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-67)

The operation is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by 4-(4-morpholinylmethy)phenylboronic acid in step 12; the sum yield of the final two steps is52%.

LCMS: 575.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.50-2.58 (br, 4H), 3.23(s, 3H), 3.72-3.78 (br, 11H), 4.18-4.32 (br, 4H), 5.18 (s, 2H), 5.20 (s,2H), 7.06 (d, 2H, J=8.4 Hz), 8.10 (d, 2H, J=8.4 Hz).

Embodiment 70 Synthesis of2-(((2-(4-chlorine)-9-methyl-6-morpholino-9H-purine-8-yl)methyl(methyl)amino)-N-hydroxylpyrimidine-5-formamide (Compound CLJ-68)

The synthesis method is the same as that of Embodiment 3, except thatstep 12 of the reaction is omitted; the target compound is obtained bymidbody 13 through step 14; the yield of the last step is 86%.

LCMS: 433.6 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 3.20 (s, 3H), 3.65 (s,7H), 3.91-4.31 (br, 4H), 5.14 (s, 2H), 8.70 (s, 2H).

Embodiment 71 Synthesis ofN-hydroxy-2-(((2-(4-methoxyphenyl)-9-methyl-6-(piperazine-1-yl)-9H-purine-8-yl)methyl)(methyl)amino)pyrimidine-5-formamide(Compound CLJ-69)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-methoxy phenylboronicacid and meanwhile morpholine ring is replaced by piperazine ring instep 6 of the reaction; the sum yield of the final two steps is 20%.

LCMS: 505.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.78-2.86 (br, 4H), 3.17(s, 4H), 3.23 (s, 3H), 3.75 (s, 3H), 3.81 (s, 3H), 5.17 (s, 2H), 7.01(d, 2H, J=8.8 Hz), 8.33 (d, 2H, J=8.8 Hz), 8.72 (s, 2H), 9.03 (s, 1H),10.01 (s, 1H), 11.09 (s, 1H).

Embodiment 72 Synthesis ofN-hydroxy-2-(((2-(4-methoxyphenyl)-9-methyl-6-(4-(2-hydroxyethylpiperazine)-1-yl)-9H-purine-8-yl)methyl)(methyl)amino)pyrimidine-5-formamide(Compound CLJ-70)

The synthesis method is the same as that of Embodiment 3, except that6-methoxypyridine-3-boronic acid is replaced by p-methoxy phenylboronicacid and meanwhile morpholine ring is replaced by 4-(2-hydroxyethylpiperazine) in step 6 of the reaction; the sum yield of the final twosteps is 27%.

LCMS: 549.3[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ: 2.53 (t, 2H, J=5, 2 Hz),3.45 (t, 2H, J=5.2 Hz), 3.2 (s, 3H), 3.47 (s, 4H), 3.62-3.70 (br, 4H),3.78 (s, 3H), 3.81 (s, 3H), 4.65 (s, 1H), 5.17 (s, 2H), 7.01 (d, 2H,J=8.8 Hz), 8.33 (d, 2H, J=8.8 Hz), 8.72 (s, 2H), 9.03 (s, 1H), 10.01 (s,1H), 11.10 (s, 1H).

Embodiment 73 Determination of the Inhibition Capability of the Compoundto the Activities of Histone Deacetylase of Subtype I (HDAC1) andPhosphoinositol 3-Kinase of all Subtypes

The following tests are used for determining the inhibition values IC₅₀of the small molecule compound of the Invention and the controlcompounds CUDC907 and LBH589 for inhibiting HDAC kinases, PI3K kinasesand mTOR.

a) In vitro test for determining the inhibition capability of thecompound to the enzymatic activity of HDAC1:

Determining the inhibition capability to HDAC activity through thesubstrate method of fluorophore 4-amino-7-coumarin coupled Ac-peptide(Lys-Ac-AMC). HDAC1 protein is purchased from BPS Bioscience Company;the reaction buffer system is a modified tris(hydroxymethyl)aminomethane(TRIS) buffer (pH7.0). All small molecule compounds are prepared anddissolved by 100% DMSO (dimethyl sulfoxide). HDAC is prepared into thebuffer as per certain concentration to be served as the enzyme solution;trypsin and the fluorophore 4-amino-7-coumarin coupled Ac-peptidesubstrate are prepared into the buffer as per certain concentration tobe served as the substrate solution. Adding the compound into thereaction wells of the 384 well plate at the designed concentration, thenadding 15 μL HDAC solution into the reaction wells (adding 15 μL blankbuffer into the control well 0) for incubation under ambient temperaturefor 15 min; then adding 10 μL substrate solution to start reaction;during the reaction, the final concentration of HDAC1 protein is 6 nM,trypsin 0.05 μM and Ac-peptide 8 μM. Keeping the 384 well plate in darkplace for incubation under ambient temperature for 1 h, then determiningthe fluorescence intensity with a microplate reader (emissionwavelength: 355 nm, absorption wavelength: 460 nm) and analyzing theresult data with the software GraphPad Prism.

Calculating the value of IC₅₀ as per the formula:Y=background data+(top data−background data)/(1+10^((Log IC50−X)*rate ofcurve))

Where, Y refers to the inhibition ratio (%) and X refers to the compoundconcentration.

b) In vitro test for determining the inhibition capability of thecompound to PI3Kα and PI3Kδ activities:

Detecting the inhibition capability of the compound to PI3Kα and PI3Kδactivities with Kinase-Glo (purchased from Promege Company; Catalog No.:V3771). PI3Kα protein is purchased from Invitrogen Company (Catalog No.:PV4788) and PI3Kδ protein is purchased from Millipore Company (CatalogNo.: 14-604-K). The reaction system also comprises substrates as PIP₂(4, 5-diphosphoinositide, purchased from Life Technologies Company) andATP (triphosadenine, purchased from Sigma Company). The reaction buffersystem comprises 50 mM HEPES (4-hydroxyethylpiperazine ethane sulfonicacid), 3 mM MgCl₂, 1 mM EGTA (ethylene glycol bis(2-aminoethylether)quadrol), 100 mM NaCl, 0.03% CHAPS(3-[3-(cholamidopropyl)dimethylamino]-1-propanesulfonic acid), 2 mM DTT(dithiothreitol). The pH value of the reaction buffer is 7.5. Preparing10 μL reaction system in corresponding wells of the 384 well plate,which contains the compositions as: the compound with designedconcentration (or blank control), protein kinases (PI3Kα, with theconcentration of 1.65 nM in PI3Kα test and PI3Kδ, with the concentrationof 5.7 nM in PI3Kδ test) and substrates (PIP₂, with the concentration of50 μM and ATP, with the concentration of 25 μM). Mixing the systemevenly for incubation under ambient temperature (for 1 h in PI3Kα testand for 2 h in PI3Kδ test). After incubation, adding 10 μL Kinase-Glowhich has been preheated to ambient temperature into each reaction wellto terminate the reaction; shaking it in dark place for 15 min after itis mixed evenly, then measuring the fluorescence intensity with amicroplate reader and analyzing the result data with the softwareGraphPad Prism.

Calculating the value of IC₅₀ as per the formula:Y=background data+(top data−background data)/(1+10^((Log IC50−X)*rate ofcurve))

Where, Y refers to the inhibition ratio (%) and X refers to the compoundconcentration.

c) In vitro test for determining the inhibition capability of thecompound to PI3Kβ and PI3Kγ activities:

Detecting the inhibition capability of the compound to PI3Kβ and PI3Kγactivities with ADP-Glo (purchased from Promege Company; Catalog No.:v9102/3). PI3Kβ protein is purchased from Millipore Company (CatalogNo.: 14-603-K) and PI3Kγ protein is purchased from Invitrogen Company(Catalog No.: PR8641C). The reaction system also comprises substrates asPIP₂ and ATP. The reaction buffer system comprises 50 mM HEPES, 3 mMMgCl₂, 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS and 2 mM DTT. The pH value ofthe reaction buffer is 7.5. Preparing 10 μL reaction system incorresponding wells of the 384 well plate, which contains thecompositions as: the compound with designed concentration (or blankcontrol), protein kinases (PI3Kβ, with the concentration of 4.8 nM inPI3Kβ test and PI3Kγ, with the concentration of 7.6 nM in PI3Kγ test)and substrates (PIP₂, with the concentration of 50 μM and ATP, with theconcentration of 25 μM). Mixing the system evenly for incubation underambient temperature for 1 h; getting a new 384 well plate andtransferring 5 μL reaction liquid from the each well of original 384well plate to the corresponding wells of the new 384 well plate; adding5 μL ADP-Glo which has been preheated to ambient temperature into eachnew reaction well to terminate the reaction; oscillating it slowly indark place for 40 min's incubation after it is mixed evenly; adding 10μL testing liquid in each reaction well, oscillating it for 1 min to mixevenly and incubating it for 1 h, then measuring the fluorescenceintensity with a microplate reader and analyzing the result data withthe software GraphPad Prism.

Calculating the value of IC₅₀ as per the formula:Y=background data+(top data−background data)/(1+10^((Log IC50−X)*rate ofcurve))

Where, Y refers to the inhibition ratio (%) and X refers to the compoundconcentration.

d) In vitro test for determining the inhibition capability of thecompound to mTOR activity:

mTOR protein is purchased from Millipore Company (Catalog No.: 14-770).The reaction buffer system comprises 50 mM HEPES, 10 mM MgCl₂, 1 mMEGTA, 3 mM MnCl, 0.01% Tween-20 (purchased from Chengdu Kelong ChemicalRegent Factory) and 2 mM DTT. The pH value of the reaction buffer is7.5. Preparing 10 μL reaction system in corresponding wells of the 384well plate, which contains the compositions as: the compound withdesigned concentration (or blank control), mTOR protein (with theconcentration of 2.5 nM), ULight-4E-BP1 (containing the 37^(th) and the46^(th) threonine residues, Thr37/46) peptide (purchased from PECompany, Catalog No.: TRF0128-M) and ATP substrates (ULight-4E-BP1peptide, with the concentration of 50 nM and ATP, with the concentrationof 10.81 μmM). Mixing it evenly for incubation under ambient temperaturefor 1 h; adding 10 μL testing liquid containing EDTA(ethylenediaminetetraacetic acid) and Eu-anti-phosphorylation-4E-BP1(Thr37/46) antibody (purchased from PE Company, Catalog No.: TRF0216-M)into the reaction wells (after the testing liquid is added, theconcentration of EDTA is 8 mM and the concentration ofEu-phosphorylation-4E-BP1 antibody is 2 nM); mixing it evenly andincubating it for 1 h under ambient temperature, then measuring thefluorescence intensity with a microplate reader and analyzing the resultdata with the software GraphPad Prism.

Calculating the value of IC₅₀ as per the formula:Y=background data+(top data−background data)/(1+10^((Log IC50−X)*rate ofcurve))

Where, Y refers to the inhibition ratio (%) and X refers to the compoundconcentration.

The compounds of the Invention and the testing results of inhibitioncapability thereof to the activities of histone deacetylase of subtype I(HDAC1), phosphoinositol 3-kinase of all subtypes (4 subtypes in total)and sirolimus of the receptor in mammal system are listed in thefollowing Table 1. The values of IC₅₀ of the results are expressedthrough the grading as: A>10 μM, 10 μM>B>1 μM, 1 μM>C>0.1 μM, 0.1μM>D>nM and E<1 nM. The reference compound CUDC907 is synthesized as perthe method^([1]) in the literature; LBH589 is purchased from SelleckCompany. The structures are:

TABLE 1 Testing results of activity inhibition capability of thecompound of the Invention Compound No. HDAC1 PI3Kα PI3Kβ PI3Kδ PI3KγmTOR CLJ-1 D B B C C B CLJ-2 D B CLJ-3 D B CLJ-4 D B CLJ-5 C D C C C CCLJ-6 C A A A A A CLJ-7 D A CLJ-8 E B CLJ-9 E A CLJ-10 D D CLJ-11 D D CC C C CLJ-12 D D C C C C CLJ-13 D D C C C C CLJ-14 D A A A A A CLJ-15 EB A A A A CLJ-16 C A CLJ-17 C A CLJ-18 D A CLJ-19 D A CLJ-20 D A CLJ-21D A CLJ-22 E A CLJ-23 D A CLJ-24 E B CLJ-25 D B CLJ-26 E A CLJ-27 E ACLJ-28 C A CLJ-29 E A CLJ-30 D A CLJ-31 C A CLJ-32 C A CLJ-33 C A CLJ-34D A CLJ-35 D A CLJ-36 E A CLJ-37 E A CLJ-38 D A CLJ-39 D A CLJ-40 D ACLJ-41 C C CLJ-42 D A CLJ-43 D A CLJ-44 E B CLJ-45 B A CLJ-46 E A CLJ-47B A CLJ-48 D A CLJ-49 D A CLJ-50 D A CLJ-51 D A CLJ-52 D A CLJ-53 D ACLJ-54 D A CLJ-55 D A CLJ-56 D A CLJ-57 E A CLJ-58 D A CLJ-59 D A CLJ-60D A CLJ-61 D A CLJ-62 D A CLJ-63 D A CLJ-64 D A CLJ-65 D A CLJ-66 D ACLJ-67 E A CLJ-68 D A CLJ-69 D A CLJ-70 D A CUDC907 D D D D C B LBH589 D

The results show that, most of above compounds have the ability toinhibit HDAC1 activity, while the inhibition value IC₅₀ ofnitrogen-containing six-membered heterocyclic compound to the activityof kinase PI3Kα is less than 0.1M; as the inhibition values IC₅₀ of thecompounds CLJ-5 and CLJ-10-CLJ-13 to the activities of HDAC1 and PI3Kαare all less than 0.1 μM, these compounds are typical bifunctionalcompounds. Partial compounds have no obvious inhibitory effect to PI3Kαactivity, but favorable inhibitory effect to HDAC activity; theinhibition values IC₅₀ of the compounds as CLJ-8, CLJ-9, CLJ-15, CLJ-22,CLJ-24, CLJ-26, CLJ-27, CLJ-29, CLJ-36, CLJ-37, CLJ-44, CLJ-46, CLJ-57and CLJ-67 to the activity of HDAC1 are less than 1 nM, therefore, theycan be used as the HDAC inhibitors with high activity. The inhibitionvalue IC₅₀ of CLJ-5 to PI3Kα activity is less than 0. μM; meanwhile,CLJ-5 has favorable inhibitory effect to activities of PI3Kβ, PI3Kδ,PI3Kγ and mTOR, therefore it is a single functional compound of PI3K.

Embodiment 74 Determination of Inhibition Capability of Compound to CellProliferation Activity

The following test is used for determining the inhibition values IC₅₀ ofthe small molecule compound of the Invention and the reference compoundsas SAHA, LBH589 and chidamide to proliferation of tumor cell linescultured in vitro.

The tumor cell lines are purchased from American Type Culture Collection(ATCC) and cultivated to the status of logarithmic growth as per thecultural method recommended by ATCC. The cells in logarithmic phase arespread on a 96 well plate as per 2000-3000/well; as foranchorage-dependent cells, the compound should be added in the testwells at certain concentration for incubation for 96 h after celladherence. Determining cell proliferation activities with method MTT fortumor cells representing solid tumor model and with method cck-8 fortumor cells representing hematologic tumor model, and analyzing theresult data with the software GraphPad Prism.

Calculating the value of IC₅₀ as per the formula:Y=background data+(top data−background data)/(1+10^((Log IC50−X)*rate ofcurve)).Where, Y refers to the inhibition ratio (%) and X refers to the compoundconcentration.

The compounds of the Invention and the inhibition capability thereof tocell proliferation activity of the tumor cell lines cultured in vitroare listed in the following Table 2. The values of IC₅₀ of the resultsare expressed through the grading as: A>1 μM, 1 μM>B>100 nM, 100 nM>C>10nM and 10 nM>D>0.1 nM. Wherein, the positive drug SAHA is purchased fromDalian Meilun Biotech Co., Ltd; LBH589 is purchased from Selleck Companyand chidamide is provided by ChipScreen Company; the structural formulasof SAHA and chidamide are as follows:

TABLE 2 Proliferation activity inhibition capability of the compounds ofthe Invention Acute myeloid leukemia Colon cancer Ovarian cancerCompound MV4-11 hct116 A2780s CLJ-1 D C D CLJ-2 B B B CLJ-3 A A A CLJ-4A A A CLJ-5 B B B CLJ-6 A A A CLJ-7 D B C CLJ-8 D C D CLJ-9 D C C CLJ-10C C B CLJ-11 D C C CLJ-12 D D D CLJ-13 D D D CLJ-14 D C D CLJ-15 C C CCLJ-16 A A A CLJ-17 A A A CLJ-18 D D C CLJ-19 D D C CLJ-20 D D C CLJ-21D D D CLJ-22 D D D CLJ-23 D D D CLJ-24 D D D CLJ-25 D D D CLJ-27 D C CCLJ-29 D D D CLJ-30 D C C CLJ-31 A A A CLJ-32 A A A CLJ-35 D C C CLJ-36D D D CLJ-38 D B C CLJ-44 D C D CLJ-48 D D D CLJ-49 C B C CLJ-54 B B BCLJ-55 D C C CLJ-56 C B B CLJ-57 D C D CLJ-60 D C D CLJ-68 C C C SAHA BB A LBH589 D D D Chidamide B A A

It is shown from the above table that the above compounds all havefavorable inhibitory effect to the proliferation activities of thetested tumor cell lines; such inhibitory effect is obviously better thanthat of positive drugs as SAHA and chidamide and some compounds evenhave the same inhibitory effect with LBH589. The values IC₅₀ of mostcompounds are 5 less than 1 μM; the compounds with the highestinhibitory effect are CLJ-12, CLJ-13, CLJ-21-CLJ-25, CLJ-29, CLJ-36 andCLJ-48, the inhibition values IC₅₀ of which to proliferation activitiesof three types of tumor cell lines are between 0.1 nM and 10 nM;meanwhile, CLJ-7 and CLJ-38 show a selective anti-tumor potential as thevalues of IC₅₀ to MV4-11 cells representing acute myeloid leukemia areless than 10 nM, while the values of IC₅₀ to hct116 cells representingcolon cancer are more than 100 nM, indicating that they may have stronginhibition capability to the activities of the tumors of specific type.

Embodiment 75 Determination of Influence of the Compounds of theInvention on Marker Protein Acetylation Level of Tumor Cells

Selecting 5 compounds CLJ-1, CLJ-8, CLJ-11, CLJ-29 and CLJ-44 as thepreferred compounds in combination with the results of Embodiments 73and 74. The following tests are used for determining the EC₅₀ of severalpreferred small molecule compounds of the Invention and the referencecompounds as SAHA, LBH589 and CUDC907 for inducing marker protein H₃ andα-tubulin acetylation in tumor cells.

Test scheme: A2780s cells from American Type Culture Collection (ATCC)are spread on a 96 well plate as per 5000 cells/well; after celladherence, treating the cells for 6 h with the compounds or the positivereference compounds as SAHA, LBH589 and CUDC907 at the concentration of1.6, 8, 40, 200 and 1000 nM respectively; then testing the proteinlevels of the acetylated histone H₃(Ac—H₃) and the acetylatedAc-α-tubulin with the method of cytoblot. Specific operation: After thetreatment, washing each well once with 50-100 μl of cold TBS buffer[with the composition as 20 mM Tris (trismetyl aminomethane), pH7.5] andfixing it with 100 μL of 4% pre-cooled paraformaldehyde at 4° C. for 1h; after paraformaldehyde is washed off, adding 50 μL of pre-cooledmethyl alcohol in each well and evenly spreading at 4° C. for 5 min;after methyl alcohol is washed off, washing it once with the TBS buffercontaining 3% skim milk powder and adding 50 μL of antibody fluid,oscillating it slightly at 4° C. and incubating overnight. Fordetermination of Ac—H₃, the antibody fluid is prepared by diluting Ac—H₃antibody and horseradish peroxide coupled secondary antibody to a samesystem with the TBS buffer containing 3% skim milk powder (Ac—H₃antibody is purchased from Santa Cruz Company and diluted at a ratio of1:100; horseradish peroxide coupled secondary antibody is purchased fromJackson Company and diluted at a ratio of 1:2000); for determination ofacetylated Ac-α-tubulin, the antibody fluid is prepared by dilutingAc-α-tubulin antibody and horseradish peroxide coupled secondaryantibody to a same system with the TBS buffer containing 3% skim milkpowder (Ac-α-tubulin antibody is purchased from Santa Cruz Company anddiluted at a ratio of 1:100; horseradish peroxide coupled secondaryantibody is purchased from Jackson Company and diluted at a ratio of1:2000). Discarding the antibody fluid in the next day and washing ittwice with TBS buffer; then adding enhanced chemiluminescence (ECL)liquid (which is purchased from Abbkine Company), determining thechemiluminescence intensity with a microplate reader, and analyzing theresult data with the software GraphPad Prism.

Calculating the value of IC₅₀ as per the formula:Y=background data+(top data−background data)/(1+10^((Log EC50−X)*rate ofcurve))Where, Y refers to the activating rate (%) and X refers to the compoundconcentration.

Several preferred compounds of the Invention and their abilities topromote the acetylation activities of histones H₃ and α-tubulin in tumorcell A2780s are listed in the following table 3. The values of EC₅₀ ofthe results are expressed through the grading as: A>200 nM, 200 nM>B>100nM and C<100 nM. Wherein, the positive drug SAHA is purchased fromDalian Meilun Biotech Co., Ltd.; LBH589 is purchased from SelleckCompany and CUDC907 is synthesized as per the method^([1]) in theliterature.

TABLE 3 Abilities of the compounds of the Invention to promote theacetylation activities of histones H₃ and α-tubulin in tumor cellsCompound Ac-Tub Ac-H₃ CLJ-1 B B CLJ-8 B B CLJ-11 B B CLJ-29 A C CLJ-44 AB LBH-589 B B CUDC907 A B SAHA A A

It is shown from Table 3 that through the determination of the abilityof the five preferred compounds in inducing acetylation activity ofmarker proteins, their inhibition capability to the activity of HDACenzyme can be verified. The abilities of the five preferred compounds ininducing acetylation activity of marker proteins are superior to that ofpositive drug SAHA and equal to those of LBH589 and CUDC907.

Embodiment 76 Determination of Inhibition Capability of the Compounds ofthe Invention to the Activities of HDAC Enzymes of all Subtypes andPhosphoinositol 3-Kinase of all Subtypes In Vitro

The following tests are used for determining the IC₅₀ of severalpreferred small molecule compounds of the Invention and the controlcompounds CUDC907 and LBH589 for inhibiting HDAC1-11 enzymes of subtypesand PI3K kinases.

Determining the inhibition capability of HDAC through the substratemethod of fluorophore coupled acetylized peptide fragment (Lys-Ac-AMC).HDAC2-11 proteins of subtypes are purchased from BPS Bioscience Companywith the Art. No. as: HDAC2, 50002; HDAC3, 50003; HDAC4, 50004; HDAC5,50005; HDAC6, 50006; HDAC7, 50007; HDAC8, 50008; HDAC9, 50009; HDAC10,50060; HDAC11, 50011. The reaction buffer system is a modified Trisbuffer (pH7.0). The small molecule compounds are prepared and dissolvedwith 100% DMSO. HDAC is prepared into the buffer as per certainconcentration to be served as the enzyme solution; in the tests forHDAC1, 2, 3, 4, 5, 6, 7 and 9 subtypes, trypsin and the fluorophore4-amino-7-coumarin coupled Ac-peptide substrate are prepared into thebuffer as per certain concentration to be served as the substratesolution; in the tests for HDAC8, 10 and 11 subtypes, the fluorophore4-amino-7-coumarin coupled Ac-peptide substrate is prepared into thebuffer as per certain concentration to be served as the substratesolution and in addition the trypsin fluid with certain concentration isprepared. Adding the compound into the reaction wells of the 384 wellplate at the designed concentration, then adding 15 μL HDAC enzymesolution into the reaction wells (adding 15 μL blank buffer into thecontrol well 0) for incubation under ambient temperature for 15 min;then adding 10 μL substrate solution to start reaction. Keeping the 384well plate in dark place for incubation under ambient temperature for 1h for the tests of HDAC1, 2, 3, 4, 5, 6, 7 and 9 subtypes, thendetermining the fluorescence intensity with a microplate reader(emission wavelength: 355 nm, absorption wavelength: 460 nm); orincubation for 3 h for the tests of HDAC8, 10 and 11 subtypes, addingtrypsin fluid into the reaction well for another 2 h's incubation indark place and then determining the fluorescence intensity with amicroplate reader. The final concentrations of the specific protease,trypsin and Ac-peptide in the test of each HDAC subtype are respectivelyas follows: For HDAC2, the concentration of protease is 4 nM, Ac-peptide10 μM and trypsin 0.05 μM; for HDAC3, the concentration of protease is 7nM, Ac-peptide 5 μM and trypsin 0.05 μM; for HDAC4, the concentration ofprotease is 0.05 nM, Ac-peptide 20 μM and trypsin 0.05 μM; for HDAC5,the concentration of protease is 1.5 nM, Ac-peptide 20 μM and trypsin0.05 μM; for HDAC6, the concentration of protease is 8 nM, Ac-peptide 11μM and trypsin 0.01 μM; for HDAC7, the concentration of protease is 0.05nM, Ac-peptide 20 μM and trypsin 0.05 μM; for HDAC8, the concentrationof protease is 150 nM, Ac-peptide 10 μM and trypsin 50 μM; for HDAC9,the concentration of protease is 0.5 nM, Ac-peptide 20 μM and trypsin0.05 μM; for HDAC10, the concentration of protease is 13 nM, Ac-peptide4 μM and trypsin 0.05 μM and for HDAC11, the concentration of proteaseis 5 nM, Ac-peptide 10 μM and trypsin 50 μM.

The method for determining the inhibition capability to the activitiesof phosphoinositide-3-kinase of all subtypes is as described in part b)and part c) in Embodiment 73.

Analyzing the result data with the software GraphPad Prism andcalculating the value of IC₅₀ as per the formula:Y=background data+(top data−background data)/(1+10^((Log IC50−X)*rate ofcurve)).Where, Y refers to the inhibition ratio (%) and X refers to the compoundconcentration.

Several preferred compounds of the Invention and the inhibitioncapability thereof to the activities of histone deacetylase of 11subtypes (HDAC1-11) and phosphoinositol 3-kinase of all subtypes arelisted in the following Table 4. The values of IC₅₀ of the results areexpressed through the grading as: A>10 μM, 10 μM>B>1 μM, 1 μM>C>0.1 μM,0.1 μM>D>1 nM and E<1 nM. Wherein, the positive drug SAHA is purchasedfrom Dalian Meilun Biotech Co., Ltd.; LBH589 is purchased from SelleckCompany and CUDC907 is synthesized as per the method^([1]) in theliterature.

TABLE 4 Inhibition capability of the compound of the Invention to theactivities of HDAC1-11 and PI3K kinases Enzyme CLJ- CLJ- CLJ- CLJ- CLJ-CUDC- LBH- subtypes 1 8 11 29 44 907 589 HDAC1 D E D E E D D HDAC2 D D DD D D D HDAC3 D D D D D D D HDAC4 B B C B B C C HDAC5 B B C B C C CHDAC6 D D D D D D D HDAC7 B C C B B C B HDAC8 C D D D D C D HDAC9 B B BB B C C HDAC10 D E D D D D D HDAC11 B C B B B D B PI3Kα B B D A B D API3Kβ B A D A A D A PI3Kγ C A D A A C A PI3Kδ C A D A A D A

It is shown from Table 4 that compounds CLJ-1, CLJ-8, CLJ-29 and CLJ-44have the same inhibition capability with the positive compounds CUDC-907and LBH589 to the activities of HDAC1, HDAC2, HDAC3 and HDAC6, HDAC8 andHDAC10; wherein, compounds CLJ-1 and CLJ-11 show a same inhibitioncapability with CUDC-907 to the double activities of HDAC1 and PI3Kkinases.

Embodiment 77 Model Tests of the Compounds of the Invention for TreatingMV4-11 Subcutaneous Tumor in Animals

Test scheme: Inoculating MV4-11 cells subcutaneously to 54 NOD/SCIDfemale mice with the inoculation amount of 10⁷ cells per mouse; when theinoculated tumor grows to 100 mm³, selecting 36 mice with uniform grosstumor volume and dividing them into 6 groups randomly. Injecting thetreatment group intravenously (i.v.) with a dose of 10 mg/kg of fivecompounds as CLJ-1, CLJ-8, CLJ-11, CLJ-29 and CLJ-44; giving SAHA, thedrug available on the market intraperitoneally (i.p.) to the positivecontrol group with a dose of 50 mg/kg; giving the control group withequal amount of blank solvent; conducting the drug administration onceper two days for 22 days' treatment. During drug administration,measuring the weight and gross tumor volume of the mice per 2 days andkeeping a record. The calculation formula is as V=π/6×A²×B, where,where, V=gross tumor volume (mm³), A=tumor width (mm) and B=tumor length(mm). Observing and keeping a record for the survival condition of thetested animals. After drug discontinuance, killing the mice throughcervical dislocation and peeling off their tumors as per the operationspecification of animal experiment. Evaluating the inhibition capabilityof the compounds to tumor activities by calculating the tumor inhibitoryrate with the formula as: tumor inhibitory rate=(1−tumor weight oftreatment group/tumor weight of control group)×100%. Analyzing andcomparing the difference between each treatment group and control groupwith the method of t-test. The grading of significance level ofdifference is: ***, P<0.001; **, P<0.01; *, P<0.05; no statisticalsignificance (ns), P>0.05.

Several preferred compounds and the results of the model tests thereoffor treating MV4-11 subcutaneous tumor in animals are listed in thefollowing Table 5. The parameters showing the results are tumorinhibitory rate, statistic difference and final survival condition.Wherein, the positive drug SAHA is purchased from Dalian Meilun BiotechCo., Ltd.

TABLE 5 Effects of the models of the compounds of the Invention fortreating MV4-11 subcutaneous tumor in animals Final survival Tumorcondition (survived Dosage inhibitory Statistic individuals/totalCompound (mg/kg) rate (%) difference individuals) CLJ-1 10 63.4 *** 5/6CLJ-8 10 64.3 *** 5/6 CLJ-11 10 45.1 ** 4/6 CLJ-29 10 65.3 *** 4/6CLJ-44 10 65.6 *** 6/6 SAHA 50 0 ns 6/6

It is shown from Table 5 that the five preferred compounds can inhibitthe growth activity of the subcutaneous tumor MV4-11; wherein, the tumorinhibitory rates of four compounds as CLJ-1, CLJ-8, CLJ-29 and CLJ-44are more than 60% under the dosage of 10 mg/kg, while the positive drugSAHA has no tumor inhibitory effect. Meanwhile, 6 tested animals ingroup compound CLJ-44 are all survived, indicating that the compound hasno obvious toxic and side effect and it is probably a most potentialcompound.

Embodiment 78 Tests for Inhibition Capability of the Compounds of theInvention to the Proliferation Activity of Multiple Hematological TumorCells

At present, the preferred development direction of HDAC inhibitors intumor therapy is to treat hematological tumor. The following test isused for determining the inhibition values IC₅₀ of several preferredcompounds of the Invention and the reference compound LBH589 toproliferation of multiple hematological tumor cell lines cultured invitro.

The tumor cells of human multiple myeloma model as U266 and RPMI-8226and the tumor cells of human B-cell lymphoma model as ramos and SUDHL-4are purchased from ATCC and cultivated to the status of logarithmicgrowth as per the cultural method recommended by ATCC; the tumor cell ofhuman multiple myeloma model as MM1S is provided by HematologyDepartment of West China Hospital of Sichuan University and cultivatedto the status of logarithmic growth as per the cultural methodrecommended by the Department; the tumor cell of human B-cell lymphomamodel as OCI-LY1 is purchased from DSMZ and cultivated to the status oflogarithmic growth as per the cultural method recommended by DSMZ; thetumor cell of human B-cell lymphoma model as HBL-1 is purchased fromRIKEN and cultivated to the status of logarithmic growth as per thecultural method recommended by RIKEN. The cells in logarithmic phase arespread on a 96 well plate as per 7,500-10,000/well; then adding thecompound into the test wells at certain concentration for incubation for96 h and determining cell proliferation activities with method cck-8,and analyzing the result data with the software GraphPad Prism.

Calculating the value of IC₅₀ as per the formula:Y=background data+(top data−background data)/(1+10^((Log IC50−X)*rate ofcurve)).Where, Y refers to the inhibition ratio (%) and X refers to the compoundconcentration.

Several preferred compounds of the Invention and the inhibitory effectthereof to the proliferation activity of multiple hematological tumorcells cultured in vitro are listed in the following Table 6. The valuesof IC₅₀ of the results are expressed through the grading as: 1 μM>A>100nM, 100 nM>B>10 nM, 10 nM>C>1 nM and 1 nM>D>0.1 nM. The positivecompound LBH589 is purchased from Selleck Company.

TABLE 6 Inhibition capability of the compounds of the Invention to theproliferation activity of multiple hematological tumor cells CompoundCLJ-1 CLJ-8 CLJ-11 CLJ-29 CLJ-44 LBH589 U266 D C B D C C RPMI-8226 C C BD D C MM1S D D C D C C OCI-LY1 B C A C B B HBL-1 C C B C C C Ramos D D BC C D SUDHL-4 C C B D C C

It is shown from Table 6 that the 5 preferred compounds have inhibitoryeffect to proliferation activities of a few tumor cell lines of humanmultiple myeloma and human B-cell lymphoma; the value of IC₅₀ is oflevel nM. Wherein, the four compounds as CLJ-1, CLJ-8, CLJ-29 and CLJ-44have equal or superior activity to positive drug LBH589.

Embodiment 79 Investigation on Inhibition Capability of Compound CLJ-44to Activities of Multiple Animal Subcutaneous Solid Tumor Models

The solid tumor model comprises human colon cancer hct116, human breastcancer MCF-7 and MDA-MB-231; the hematological tumor model compriseshuman multiple myeloma MM1S and human B-cell lymphoma Raji.

1) Laboratory animal: positive drug LBH589 purchased from SelleckCompany; SPF female nude mice BALB/c (Balb/C nu/nu), 4-6 weeks old,18-22 g and NOD/SCID female mice, 6-8 weeks old, purchased from BeijingHuafukang Biotechnology Co., Ltd. Production Permit No.: SCXK (J)2014-0012. Test condition: SPF animal room; Laboratory Animal UsageLicense No.: SYXK (J) 2015-0023

2) Cell source and culture

Human colon cancer hct116, human breast cancer MCF-7 and MDA-MB-231 andhuman B-cell lymphoma Raji are purchased from ATCC, the breed of whichis conserved in the State Key Laboratory of Biotherapy, SichuanUniversity; human multiple myeloma cell strain MM1S is provided byHematology Department of West China Hospital of Sichuan University andsubcultured in the State Key Laboratory of Biotherapy, SichuanUniversity. Cell MM1S is cultured in RPMI1640 medium (HyClone) whichcontains 10% fetal calf serum (Hohhot Caoyuan Lvye BioengineeringMaterial Co., Ltd.) and 100 U/mL penicillin and streptomycin (Beyotime).

3) Inoculation, grouping and treatment: collecting cells in logarithmicphase under aseptic conditions and counting; diluting the single cellsuspension with the medium containing neither fetal calf serum norantibiotics to 1×10⁷-8 cell/mL for standby. Mixing the cell suspension;injecting 100 μL of cell suspension (5×10⁶-2×10⁷ cells) subcutaneouslywith a 1 mL injector on the right side of the back of animals. Weedingout the animals with oversized and undersized tumor when the tumor growsto an average volume of about 120 mm³ and grouping the qualified animalsfor treatment and drug administration. Refer to Table 7 for eachgrouping model and drug administration frequency. Measuring the weightof each model per 2 days and measuring the length and width of the tumorwith a vernier caliper; killing the tested animals through cervicaldislocation and peeling off their tumors for weight measuring andphotographing. Then calculating the tumor inhibition ratio (%) andevaluating the inhibition intensity to tumor with such tumor inhibitionratio. The treatment effect of the compound CLJ-44 to each model islisted in the following Table 7.

TABLE 7 Summary of treatment effects of the compound CLJ-44 to varioustumor models Method of administration Tumor Dosage Inhibitory modelCompound (mg/kg) Frequency Approach Death rate (%) hct116 Blank — Onceper Intravenous 0/6 — control 2 days administration CLJ-44 2.5 Once perIntravenous 0/6 49.4 2 days administration CLJ-44 5 Once per Intravenous0/6 53.3 2 days administration CLJ-44 10 Once per Intravenous 0/6 68.2 2days administration SAHA 50 Once per Intraperitoneal 0/6 32.4 2 daysadministration MCF-7 Blank — Once per Intravenous 0/6 — control 2 daysadministration CLJ-44 2.5 Once per Intravenous 0/6 69.58 2 daysadministration CLJ-44 5 Once per Intravenous 0/6 77.58 2 daysadministration CLJ-44 10 Once per Intravenous 0/6 82.24 2 daysadministration Paclitaxel 30 Once per Intraperitoneal 0/6 77.73 7 daysadministration LBH589 10 Once per Intraperitoneal 0/6 75.69 2 daysadministration MDA-MB-231 Blank — Once per Intravenous 0/6 NA control 2days administration CLJ-44 2.5 Once per Intravenous 0/6 72.1 2 daysadministration CLJ-44 5 Once per Intravenous 0/6 83.9 2 daysadministration CLJ-44 10 Once per Intravenous 0/6 86.9 2 daysadministration Paclitaxel 30 Once per Intraperitoneal 0/6 59.19 7 daysadministration LBH589 10 Once per Intraperitoneal 0/6 77.95 2 daysadministration MM1S Blank — Once per Intravenous 0/7 control 2 daysadministration CLJ-44 2.5 Once per Intravenous 0/7 45.09 2 daysadministration CLJ-44 5 Once per Intravenous 0/7 69.65 2 daysadministration CLJ-44 10 Once per Intravenous 0/7 71.94 2 daysadministration LBH589 10 Once per Intraperitoneal 0/7 47.33 2 daysadministration Raji Blank — Once per 0/6 NA control 2 days CLJ-44 5 Onceper Intraperitoneal 0/6 76.96 2 days administration CLJ-44 10 Once perIntraperitoneal 0/6 97.34 2 days administration CLJ-44 20 Once perIntraperitoneal 0/6 99.29 2 days administration LBH589 10 Once perIntraperitoneal 0/6 54.93 2 days administration

It is shown from Table 7 that, the compound CLJ-44 has favorableinhibitory effect to the tumor activities of various human subcutaneoustransplantation tumor models (including colon cancer, breast cancer,multiple myeloma and B-cell lymphoma). It has good interdependencebetween dosage and tumor inhibitory rate in each model and theinhibition capability to tumor activity is obviously better than thereference drugs SAHA and LBH589.

REFERENCES

-   [1] Qian, C., et al., Cancer network disruption by a single molecule    inhibitor targeting both histone deacetylase activity and    phosphatidylinositol 3-kinase signaling. Clin Cancer Res, 2012.    18(15): p. 4104-13.

The invention claimed is:
 1. A compound of Formula I:

wherein, X is O or N—R′; R′ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy or an alkylsubstituted by C₁-C₄ hydroxy; R₁ is C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH,halogen, C₃-C₈ cycloalkyl, —NH₂,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen; or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein: X is O or N—R′; R′ is —H or analkyl substituted by C₁-C₄ hydroxy; R₁ is C₁-C₄ alkyl, C₁-C₄ alkoxy,—OH, halogen, C₃-C₈ cycloalkyl, —NH₂,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently-H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 3. The compound according to claim 2, wherein: R₁ ishalogen, C₃-C₈ cycloalkyl, —NH₂,

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₂and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen orC₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 4. The compound according to claim 3, wherein: R₁ ishalogen,

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₂and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen orC₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 5. The compound according to claim 4, wherein: R₁ is—Cl,

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₂and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen orC₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy,—OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 6. The compound according to claim 2, wherein: R₂ and R₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy or C₃-C₈ cycloalkyl; Xis O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 7. The compound according to claim 6, wherein: R₂ and R₃are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; X is O or N—R′;R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 8. The compound according to claim 7, wherein: R₂ and R₃are independently —H, C₁-C₄ alkyl or cyclopentyl alkyl; X is O or N—R′;R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 9. The compound according to claim 2, wherein: R₄-R₉ areindependently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₈ cycloalkyl, —NH₂,—COOH, C₁-C₄ alkyl amino or

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 10. The compound according to claim 9, wherein: R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 11. The compound according to claim 10, wherein: R₄-R₉are independently —H, C₁-C₄ alkyl, methoxyl, —NH₂, —COOH, methylamino or

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 12. The compound according to claim 2, wherein: R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxyR₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 13. The compound according to claim 12, wherein: R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄hydroxy; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 14. The compound according to claim 2, wherein: R₁₄ andR₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; X is O or N—R′; R′ is —H or an alkylsubstituted by C₁-C₄ hydroxy; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 15. The compound according to claim 14, wherein: R₁₄ andR₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

OH or halogen.
 16. The compound according to claim 2, wherein: R₁₆ isC₁-C₄ alkyl,

X is O or N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₇ is —NH₂,

—OH or halogen.
 17. The compound according to claim 16, wherein: X is Oor N—R′; R′ is —H or an alkyl substituted by C₁-C₄ hydroxy; R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,


18. The compound according to claim 2, wherein: X is O or N—R′; R′ is —Hor hydroxy ethyl; R₁ is —Cl,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or cyclopentyl alkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, methoxy, —NH₂, —COOH, methylamino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, methoxy, —OH, —CF₃, —Cl,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,


19. The compound according to claim 1, wherein: when X is O, thestructure of which is as shown in Formula II:

wherein, R₁ is C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen, C₃-C₈cycloalkyl, —NH₂,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 20. The compound according to claim 19, wherein: R₁ ishalogen, C₃-C₈ cycloalkyl, —NH₂,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 21. The compound according to claim 20, wherein: R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 22. The compound according to claim 21, wherein: R₁ is—Cl,

R₂ and R₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogenor C₃-C₈ cycloalkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —OH, halogen, C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl aminoor

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 23. The compound according to claim 19, wherein: R₂ andR₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy or C₃-C₈ cycloalkyl;R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 24. The compound according to claim 23, wherein: R₂ andR₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 25. The compound according to claim 24, wherein: R₂ andR₃ are independently —H, C₁-C₄ alkyl or cyclopentyl alkyl; R₁ ishalogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 26. The compound according to claim 19, wherein: R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₈ cycloalkyl, —NH₂,—COOH, C₁-C₄ alkyl amino or

R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 27. The compound according to claim 26, wherein: R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 28. The compound according to claim 27, wherein: R₄-R₉are independently —H, C₁-C₄ alkyl, methoxy, —NH₂, —COOH, methylamino or

R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 29. The compound according to claim 19, wherein: R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 30. The compound according to claim 29, wherein: R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; R₁ is halogen,

R₂ and R₃ are independently C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉ areindependently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄ alkylamino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 31. The compound according to claim 19, wherein: R₁₄ andR₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 32. The compound according to claim 31, wherein: R₁₄ andR₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 33. The compound according to claim 19, wherein: R₁₆ isC₁-C₄ alkyl,

R₁ is halogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₇ is —NH₂,

—OH or halogen.
 34. The compound according to claim 19, wherein: R₁ ishalogen,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,


35. The compound according to claim 34, wherein: preferably, R₁ is —Cl,

R₂ and R₃ are independently —H, C₁-C₄ alkyl or cyclopentyl alkyl; R₄-R₉are independently —H, C₁-C₄ alkyl, methoxy, —NH₂, —COOH, methylamino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, methoxy, —OH, —CF₃, —Cl,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,


36. The compound according to claim 19, wherein: when R₂ is methyl, thestructure of which is as shown in Formula III:

wherein, R₁ is C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen, C₃-C₈cycloalkyl, —NH₂,

R₃ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen or C₃-C₈ cycloalkyl;R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 37. The compound according to claim 36, wherein: R₁ ishalogen, C₃-C₈ cycloalkyl, —NH₂,

R₃ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen or C₃-C₈ cycloalkyl;R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 38. The compound according to claim 37, wherein: R₁ ishalogen,

R₃ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen or C₃-C₈ cycloalkyl;R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 39. The compound according to claim 38, wherein: R₁ is—Cl,

R₃ is —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen or C₃-C₈ cycloalkyl;R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 40. The compound according to claim 36, wherein: R₃ is—H, C₁-C₄ alkyl, C₁-C₄ alkoxy or C₃-C₈ cycloalkyl; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 41. The compound according to claim 40, wherein: R₃ is—H, C₁-C₄ alkyl or C₃-C₈ cycloalkyl; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 42. The compound according to claim 41, wherein: R₃ is—H or C₁-C₄ alkyl; R₁ is halogen,

R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, halogen,C₃-C₈ cycloalkyl, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, C₃-C₈ cycloalkyl, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

or halogen.
 43. The compound according to claim 36, wherein: R₄-R₉ areindependently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₈ cycloalkyl, —NH₂,—COOH, C₁-C₄ alkyl amino or

R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl,C₁-C₄ alkoxy, —OH, —CF₃, halogen, C₃-C₈ cycloalkyl, —NH₂, an alkylsubstituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 44. The compound according to claim 43, wherein: R₄-R₉are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —NH₂, —COOH, C₁-C₄alkyl amino or

R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl,C₁-C₄ alkoxy, —OH, —CF₃, halogen, C₃-C₈ cycloalkyl, —NH₂, an alkylsubstituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 45. The compound according to claim 44, wherein: R₄-R₉are independently —H, C₁-C₄ alkyl, methoxy, —NH₂, —COOH, methylamino or

R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl,C₁-C₄ alkoxy, —OH, —CF₃, halogen, C₃-C₈ cycloalkyl, —NH₂, an alkylsubstituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 46. The compound according to claim 36, wherein: R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 47. The compound according to claim 46, wherein: R₁₀-R₁₃are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃, halogen,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 48. The compound according to claim 36, wherein: R₁₄ andR₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl,

C₁-C₄ alkoxy or halogen; R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 49. The compound according to claim 48, wherein: R₁₄ andR₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₆ is C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,

R₁₇ is —NH₂,

—OH or halogen.
 50. The compound according to claim 36, wherein: R₁₆ isC₁-C₄ alkyl,

R₁ is halogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₇ is —NH₂,

—OH or halogen.
 51. The compound according to claim 36, wherein: R₁ ishalogen,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl, C₁-C₄alkoxy, —NH₂, —COOH, C₁-C₄ alkyl amino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, C₁-C₄ alkoxy, —OH, —CF₃,halogen, —NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1-4; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,


52. The compound according to claim 36, wherein: R₁ is —Cl,

R₃ is —H or C₁-C₄ alkyl; R₄-R₉ are independently —H, C₁-C₄ alkyl,methoxy, —NH₂, —COOH, methylamino or

R₁₀-R₁₃ are independently —H, C₁-C₄ alkyl, methoxy, —OH, —CF₃, —Cl,—NH₂, an alkyl substituted by C₁-C₄ hydroxy,

n=1 or 2; R₁₄ and R₁₅ are independently —H, C₁-C₄ alkyl, C₁-C₆ alkenyl,

t-butyloxycarboryl or

R₁₆ is C₁-C₄ alkyl,

R₁₇ is —NH₂,


53. The compound according to claim 1, having a structure selected fromthe following group:

or a pharmaceutically acceptable salt thereof.
 54. A pharmaceuticalcomposition comprising pharmaceutically acceptable auxiliary ingredientsand the compound according to claim 1 or a pharmaceutically acceptablesalt thereof.
 55. The pharmaceutical composition of claim 54, which isprovided in a form of an oral preparation or an intravenous injectionpreparation.